Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes

Article (PDF Available)inHepatology 56(3):952-60 · September 2012with38 Reads
Impact Factor: 11.06 · DOI: 10.1002/hep.25741 · Source: PubMed
Unlabelled: Fructose consumption predicts increased hepatic fibrosis in those with nonalcoholic fatty liver disease (NAFLD). Because of its ability to lower hepatic adenosine triphosphate (ATP) levels, habitual fructose consumption could result in more hepatic ATP depletion and impaired ATP recovery. The degree of ATP depletion after an intravenous (IV) fructose challenge test in low- versus high-fructose consumers was assessed. We evaluated diabetic adults enrolled in the Action for Health in Diabetes Fatty Liver Ancillary Study (n = 244) for whom dietary fructose consumption estimated by a 130-item food frequency questionnaire and hepatic ATP measured by phosphorus magnetic resonance spectroscopy and uric acid (UA) levels were performed (n = 105). In a subset of participants (n = 25), an IV fructose challenge was utilized to assess change in hepatic ATP content. The relationships between dietary fructose, UA, and hepatic ATP depletion at baseline and after IV fructose challenge were evaluated in low- (<15 g/day) versus high-fructose (≥ 15 g/day) consumers. High dietary fructose consumers had slightly lower baseline hepatic ATP levels and a greater absolute change in hepatic α-ATP/ inorganic phosphate (Pi) ratio (0.08 versus 0.03; P = 0.05) and γ-ATP /Pi ratio after an IV fructose challenge (0.03 versus 0.06; P = 0.06). Patients with high UA (≥ 5.5 mg/dL) showed a lower minimum liver ATP/Pi ratio postfructose challenge (4.5 versus 7.0; P = 0.04). Conclusions: High-fructose consumption depletes hepatic ATP and impairs recovery from ATP depletion after an IV fructose challenge. Subjects with high UA show a greater nadir in hepatic ATP in response to fructose. Both high dietary fructose intake and elevated UA level may predict more severe hepatic ATP depletion in response to fructose and hence may be risk factors for the development and progression of NAFLD.

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Available from: Edward W Lipkin, Nov 24, 2014
Higher Dietary Fructose Is Associated With Impaired
Hepatic Adenosine Triphosphate Homeostasis in
Obese Individuals With Type 2 Diabetes
Manal F. Abdelmalek,
Mariana Lazo,
Alena Horska,
Susanne Bonekamp,
Edward W. Lipkin,
Ashok Balasubramanyam,
John P. Bantle,
Richard J. Johnson,
Anna Mae Diehl,
Jeanne M. Clark
and the Fatty Liver Subgroup of the Look AHEAD Research Group
Fructose consumption predicts increased hepatic fibrosis in those with nonalcoholic fatty
liver disease (NAFLD). Because of its ability to lower hepatic adenosine triphosphate
(ATP) levels, habitual fructose consumption could result in more hepatic ATP depletion
and impaired ATP recovery. The degree of ATP depletion after an intravenous (IV) fruc-
tose challenge test in low- versus high-fructose consumers was assessed. We evaluated dia-
betic adults enrolled in the Action for Health in Diabetes Fatty Liver Ancillary Study (n 5
244) for whom dietary fructose consumption estimated by a 130-item food frequency
questionnaire and hepatic ATP measured by phosphorus magnetic resonance spectroscopy
and uric acid (UA) levels were performed (n 5 105). In a subset of participants (n 5 25),
an IV fructose challenge was utilized to assess change in hepatic ATP content. The rela-
tionships between dietary fructose, UA, and hepatic ATP depletion at baseline and after IV
fructose challenge were evaluated in low- (<15 g/day) versus high-fructose (15 g/day)
consumers. High dietary fructose consumers had slightly lower baseline hepatic ATP levels
and a greater absolute change in hepatic a-ATP/ inorganic phosphate (Pi) ratio (0.08 ver-
sus 0.03; P 5 0.05) and c-ATP /Pi ratio after an IV fructose challenge (0.03 versus 0.06;
P 5 0.06). Patients with high UA (5.5 mg/dL) showed a lower minimum liver ATP/Pi
ratio postfructose challenge (4.5 versus 7.0; P 5 0.04). Conclusions: High-fructose
consumption depletes hepatic ATP and impairs recovery from ATP depletion after an IV
fructose challenge. Subjects with high UA show a greater nadir in hepatic ATP in response
to fructose. Both high dietary fructose intake and elevated UA level may predict more
severe hepatic ATP depletion in response to fructose and hence may be risk factors for the
development and progression of NAFLD.
(HEPATOLOGY 2012;56:952-960)
he increasing prevalence of nonalcoholic fatty
liver disease (NAFLD) parallels the rise in obe-
sity and type 2 diabetes mellitus (T2DM).
Patients with obesity and T2DM have not only a
higher prevalence, but also more severe forms of
NAFLD (i.e., steatohepatitis, hepatic fibrosis, or cir-
The rapid rise in NAFLD supports the role
for environmental factors, which, in tandem with pre-
disposing genetic factors, likely contribute to the
pathogenesis and epidemic of NAFLD. In recent
Abbreviations: ADP, adenosine diphosphate; ALT, alanine aminotransferase; AMP, adenosine monophosphate; AMPK, adenosine monophosphate kinase; ATP,
adenosine triphosphate; BMI, body mass index; CLD, chronic liver disease; FFQ, food frequency questionnaire; Hb1Ac, glycosylated hemoglobin; HFCS, high-
fructose corn syrup; IR, insulin resistance; IV, intravenous; Look AHEAD, Action for Health in Diabetes Study; MR, magnetic resonance; MRS, magnetic resonance
spectroscopy; NAFLD, nonalcoholic fatty liver disease;NCI, National Cancer Institute; PDEs, phosphodiesters; Pi, inorganic phosphate; PMEs, phosphomonoesters;
P MRS, phosphorous magnetic resonance spectroscopy; T2DM, type 2 diabetes mellitus; UA, uric acid.
From the
Division of Gastroenterology and Hepatology, Duke University, Durham, NC;
Department of Epidemiology,
Russel H. Morgan Department of Radiology
and Radiological Science, and
Department of Medicine, Johns Hopkins University, Baltimore, MD;
Division of Metabolism, Endocrinology, and Nutrition,
University of Washington, Seattle, WA;
Division of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, TX;
Division of Endocrinology
and Diabetes, University of Minnesota, Minneapolis, MN; and
Division of Nephrology, University of Colorado, Denver, CO.
Received October 17, 2011; accepted February 18, 2012.
The study was supported by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disorders (NIH/NIDDK; grant nos.:
RO1-DK060427 and UO1-DK57149) and the John Hopkins University School of Medicine General Clinical Research Center (M01-RR00052). R.J.J. is
supported by grant HL-68607. M.F.A. is supported by a NIH/NIDDK K23 Career Development Award (K23-DK062116).
This study was presented at the American Association for the Study of Liver Diseases 60th Annual Meeting, Boston, MA, October 30-November 3, 2009.
Page 1
decades, there has not only been an increase in total
energy consumption, but also a shift in the types of
nutrients consumed.
Fructose is a simple monosaccharide found in plant
sources. Most commercially available fructose is in the
form of a disaccharide (i.e., mixture of glucose and
fructose) in the form of high-fructose corn syrup
(HFCS). In the United States, fructose consumption
has more than doubled in the past 30 years and has
paralleled the rise in obesity and T2DM.
1900, Americans consumed approximately 15 g of
fructose per day (4% of total calories), mainly through
fruits and vegetables. However, by 1994, Americans
consumed approximately 55 g of fructose per day
(10% of total calories),
which is primarily accounted
for by the marked increase in soft-drink consump-
Despite conservative estimates, patients with
NAFLD consume 2- to 3-fold more fructose-contain-
ing beverages than matched controls.
The parallel
trend in rise of obesity, T2DM, NAFLD, and fructose
consumption makes fructose an attractive target for
Fructose induces both metabolic syndrome and
NAFLD independent of energy intake.
In fact, free
fructose and glucose combinations (such as seen with
HFCS) induce fatty liver more than sucrose, despite
the same fructose content.
In overweight or obese
adults, consumption of fructose-sweetened, but not
glucose-sweetened, beverages increases de novo lipogen-
esis, promotes dyslipidemia, impairs insulin sensitivity,
and increases visceral adiposity.
Furthermore, a longi-
tudinal study of women (n ¼ 91,249) followed up
over 8 years showed that those who consumed 1
serving of soft drinks per day were at twice the risk of
developing T2DM as those who consumed <1 serving
per month.
Thus, it is plausible that habitual and/or
excessive fructose consumption may not only increase
the risk for NAFLD,
but also exacerbate liver
injury and promote fibrosis progression in NAFLD.
Unlike glucose metabolism, there is no negative
feedback mechanism regulating the phosphorylation of
fructose to prevent hepatic adenosine triphosphate
(ATP) depletion.
Upon entering the hepatocyte,
fructose is rapidly phosphorylated by fructokinase to
generate fructose-1-phosphate. Fructose-induced he-
patic ATP depletion has been demonstrated with low
concentrations of fructose (1 mM) in a variety of cell
and in humans by both phosphorus mag-
netic resonance spectroscopy (
and by
liver biopsy.
Cellular ATP depletion can cause an
arrest in protein synthesis and induce inflammatory
and pro-oxidative changes.
Consistent with
these findings, HFCS increases fatty acid synthesis,
increases endoplasmic reticulum stress, promotes acti-
vation of the stress-related kinase, Jun N-terminal ki-
nase, induces mitochondrial dysfunction, and increases
apoptotic activity
in liver cells. Habitual fructose
consumption may therefore lead to an unfavorable
energy balance in the liver, thus enhancing the suscep-
tibility of hepatocytes to injury.
Fructose metabolism also causes rapid intracellular
generation of uric acid (UA). When fructose is rapidly
phosphorylated, intracellular phosphate levels fall,
resulting in the stimulation of adenosine monophos-
phate (AMP) deaminase. Consequently, the increased
stimulation of AMP deaminase shunts AMP toward
the production of UA, as opposed to the regeneration
of ATP by AMP kinase (AMPK).
After fructose
ingestion, serum UA can increase by 1-4 mg/dL within
30 minutes.
Furthermore, in subjects who chroni-
cally consume a high-fructose diet, fructose administra-
tion results in an enhanced rise in serum UA.
increased UA may serve as a biomarker for increased
fructose consumption and, potentially, as a marker of
hepatic ATP depletion. Recent studies also suggest that
UA may itself have proinflammatory and -oxidative
that could be involved in the development
and progression of NAFLD.
Finally, both cell-cul-
ture and experimental studies suggest that the continu-
ous exposure to fructose results in the up-regulation of
both transporters (e.g., Glut5) and enzymes (e.g., fruc-
tokinase) involved in fructose metabolism.
ent with these data, subjects with NAFLD had higher
hepatic fructokinase messenger RNA (mRNA) levels,
compared to subjects with other forms of chronic liver
disease (CLD).
We proposed the following hypotheses. First, sub-
jects with higher habitual intake of fructose may be
susceptible to lower ATP levels. Second, subjects with
higher UA levels (either as a consequence of increased
Address reprint requests to: Manal F. Abdelmalek, M.D., M.P.H., Division of Gastroenterology and Hepatology, Duke University Medical Center, P.O. Box
3913, Durham, NC 27710. E-mail: manal.abdelmalek@duke.edu; fax: (919) 684-8857.
2012 by the American Association for the Study of Liver Diseases.
View this article online at wileyonlinelibrary.com.
DOI 10.1002/hep.25741
Potential conflict of interest: R.J.J. published a lay book (‘The Sugar Fix’) that discusses the potential role of fructose in obesity and fatty liver and has a patent
application on lowering uric acid to reduce fatty liver disease.
HEPATOLOGY, Vol. 56, No. 3, 2012 ABDELMALEK ET AL. 953
Page 2
fructose consumption or as a surrogate marker of
impaired hepatic energy homeostasis) may be at
increased risk for hepatic ATP depletion from
increased dietary consumption of fructose. To test
these hypotheses, we evaluated the relationship of die-
tary fructose consumption and baseline UA levels to
the baseline, nadir, and duration of hepatic ATP deple-
tion by
P MRS in a subset (n ¼ 25) of subjects en-
rolled in the Action for Health in Diabetes (Look
AHEAD) Fatty Liver Ancillary Study.
Patients and Methods
Human Subjects. The design and methods of the
Look AHEAD study have been previously described.
All participants were recruited by means of public ad-
vertisement and under went complete medical histor y,
examination, and laboratory tests to exclude viral hepa-
titis and other major diseases. Participants were eligible
if they were between the ages of 45 and 76 years, had
T2DM, a body mass index (BMI) 25 kg/m
, and
were able to complete a maximal exercise test. Exclu-
sion criteria included known CLD, cirrhosis, inflam-
matory bowel disease requiring treatment in the past
year, consumption of >14 alcoholic drinks per week,
previous bariatric surgery or use of weight-loss medica-
tions, uncontrolled medical conditions (e.g., glycosyla-
ted hemoglobin [HbA1c] >11% or blood pressure
160/100 mm/Hg), use of systemic corticosteroids,
known conditions that would limit their lifespan (e.g.,
cancer), or their adherence to the study protocol (e.g.,
inability to engage in moderate exercise). Participants
who weighed over 350 pounds or who had any contra-
indication to magnetic resonance (MR) imaging were
excluded from the MR portion of the study. Between
January 2002 and April 2004, 244 Look AHEAD
study subjects enrolled at Johns Hopkins University
(Baltimore, MD) also participated in the Look
AHEAD Fatty Liver Ancillary Study. Informed consent
was obtained from each participant included in the
study, which was approved by the institutional review
Experimental Protocol. As a part of both the par-
ent Look AHEAD trial, participants underwent exten-
sive data collection at baseline and screening. Age, sex,
race/ethnicity, and medication use were obtained by
questionnaire. Lifetime alcohol use was estimated using
the validated Skinner Lifetime Drinking History ques-
Weight, height, and waist circumference
were directly measured using standardized techniques.
Blood samples were obtained in all patients after an
overnight fast and included UA, serum aminotransfer-
ases, Hb1Ac, creatinine, and lipid levels. Serum UA
was quantified by an autoanalyzer.
Usual food and nutrient intake in the preceding 6
months were obtained using a food frequency ques-
tionnaire (FFQ) modified slightly from the Diabetes
Prevention Program FFQ. Estimates of food and nutri-
ent intake were conducted by the Look AHEAD Diet
Assessment Center using the National Cancer Institute
(NCI) Health Habits and History Questionnaire/
DietSys program (version 3.0, 1993; NCI, Rockville,
MD), and the dataset was provided to the Look
AHEAD Data Coordinating Center. The nutrient
database was modified from the Diabetes Prevention
Program database to incorporate new foods added for
the Look AHEAD FFQ.
Nutrient values for the
added foods were obtained primarily from the Nutri-
tion Data System for Research (version 4.01_30,
1999; Nutrition Coordination Center, Minneapolis,
H and
P MRS were carried out on a 1.5-T whole
body scanner (Philips Gyroscan ACS-NT; Philips
Medical Systems, Best, The Netherlands), and hepatic
fat and ATP were measured as previously reported.
H MR spectra were processed in the frequency do-
main using an in-house software program, ‘‘CSX’
(http://mri.kennedykrieger.org/). Areas under the water
and fat signals were determined by integration after
zero filling to 2,048 data points and exponential
broadening of 3 Hz. Percentage of hepatic fat was
determined according to fat * 100/(water þ fat).
spectra data were processed using a circle-fitting
(CFIT) program, as previously described.
35 31
allows for reproducible quantification and of phospho-
rus-containing metabolites.
detected in six resonances (i.e., phosphomonoesters
[PMEs], inorganic phosphate [Pi], phosphodiesters
[PDEs], and the nucleotide triphosphates, including c,
a, and b signals) resolved sequentially. These latter
three peaks are commonly referred to as ATP signals,
although the c and a signals may include adenosine
diphosphate (ADP), and uridine, guanosine, inosine,
and cytosine triphosphates contribute to these signals
as well.
‘Hepatic ATP’ was expressed as b-ATP/total
A representative smaller sample (n ¼ 25) of partici-
pants underwent a fructose challenge test,
in the morning (between 6:30 a.m. and 9:30 a.m.) af-
ter an overnight fast. After intravenous (IV) catheter
placement, a slow infusion of isotonic saline solution
was started. After two baseline
P MR spectra were
obtained, fructose (250 mg/kg of body weight), dis-
solved in 100 mL of isotonic saline solution, was
Page 3
rapidly infused over 30-60 seconds; further spectra
were then collected every 5 minutes for 1 hour. The
slow saline infusion was continued until the end of the
study. Of the 25 subjects who underwent a fructose
challenge test, 16 subjects had FFQ and an assessment
of UA.
Statistical Analysis. This pilot study was conducted
as exploratory hypothesis-generating research to assess
whether hepatic ATP depletion and/or UA levels may
be associated with increased dietary fructose consump-
tion and response to IV fructose challenge. As a result
of convenience sampling, this study could not be suffi-
ciently powered to judge significance. We restricted
our analyses to the 16 individuals with data on fruc-
tose intake, UA, and dynamic
P MRS. We defined
‘high fructose consumption as fructose consumption
>15 g/day, a threshold in keeping with dietary fruc-
tose intake from vegetables and grains alone.
For all
the analyses, we also used tertiles of fructose and fruc-
tose as continuous variables. Hyperuricemia was
defined as UA >5.5 mg/dL. Differences in baseline
hepatic ATP (ß-ATP/total phosphorus), nadir value of
ATP, and recovery by fructose consumption (high ver-
sus low) and UA level (hyperuricemia versus normal)
were assessed using nonparametric tests because of the
non-normal distribution of
P MRS data and the
small sample size. Differences in other
P MRS pa-
rameters (e.g., a-ATP/Pi, b-ATP/Pi, c-ATP/Pi, PME/
Pi, and PDE/Pi) were also evaluated and compared
among the groups. All statistical analyses were con-
ducted using Stata 9.2 software (StataCorp LP, College
Station, TX) and SAS 9.1 software (SAS Institute,
Cary, NC) and were not performed at the Look
AHEAD Data Coordinating Center. Differences were
considered statistically significant when P values were
less than 0.05. A ‘borderline’ P value of 0.06 was
considered noteworthy of consideration as a trend to-
ward significance.
Clinical Characteristics of the Study
Population. Of those enrolled in the Look AHEAD
Fatty Liver Ancillary Study (n ¼ 244), 25 subjects had
a successful magnetic resonance spectroscopy (MRS)
and completed an IV fructose challenge test. With the
exception of lower BMI and total caloric intake, our
study cohort was comparable in age, gender, serum
UA, total fructose intake, percent liver fat, liver bio-
chemistries, or use of insulin-sensitizing agents, com-
pared to those Look AHEAD subjects who did not
undergo an IV fructose challenge test (Table 1).
NAFLD (defined as >5% hepatic fat by MRS) was
noted in 16 of 25 (64%) subjects. Among those with
NAFLD, fat content ranged from 5% to 29%. Average
fructose consumption in the high- versus low-fructose
group was 22.3 6 1.95 versus 11.13 6 1.33 g/day
(P < 0.001). Total energy intake in the high- versus
low-fructose group was 1,716 6 242 versus 1,497 6
160 calories per day (P ¼ 0.046). In the study cohort,
serum UA in subjects with high versus low UA was
6.39 6 0.25 versus 4.35 6 0.18 mg/dL (P < 0.001).
Summary of the Results of the ATP Fructose Chal-
lenge Test. Of the 25 patients who completed the IV
fructose challenge test, patients with high dietary fruc-
tose consumption had lower mean hepatic ATP and
ATP/total phosphate ratio at baseline, as compared to
those who consumed lower amounts of fructose (Fig.
1). Patients who consumed higher amounts of fructose
Table 1. Characteristics of Participants Who Completed a
Fructose Challenge Test
IV Fructose Challenge Test
P Value
Not Completed
(N ¼ 219)
(N ¼ 25)
Age, years 61.1 (6.1) 60.3 (7.1) 0.580
Gender, % female 52 58 0.450
Race, % white/other 68 88 0.200
BMI, kg/m
36.3 (6.0) 32.9 (3.0) 0.001
Serum uric acid, mg/dL 5.2 (1.3) 4.9 (1.2) 0.760
Total calorie intake,
1,950 (1,391, 2,591) 1,502 (1,182, 1,771) 0.010
Fructose g/day 16.8 (11.4, 24.3) 17.1 (12.7-24.0) 0.640
Liver outcomes
Steatosis, % liver fat 5.2 (2.4, 11.6) 5.8 (3.9, 16.1) 0.140
ALT 21 (16, 28) 23 (18, 31) 0.310
AST 18 (15, 23) 22 (18, 25) 0.080
Use of metformin, % 48 46 0.980
Use of
thiazolidinediones, %
31 50 0.070
Use of insulin, % 16 0 0.020
Abbreviation: AST, aspartamine aminotransferase.
Fig. 1. Response to IV fructose challenge, by fructose intake.
HEPATOLOGY, Vol. 56, No. 3, 2012 ABDELMALEK ET AL. 955
Page 4
also had lower b-ATP/Pi and c-ATP/Pi at nadir and
50 minutes after the IV fructose challenge. Similarly,
at baseline, patients with hyperuricemia had lower
mean baseline hepatic ATP levels as well as lower ATP
levels at the nadir and 50 minutes after IV fructose
challenge. The mean hepatic ATP/total phosphate ratio
in patients with hyperuricemia dropped further than
in patients without hyperuricemia (P ¼ 0.04), suggest-
ing less hepatic ‘reserve’ (Fig. 2), although levels at
baseline and at recovery were comparable.
Changes in
P MRS metabolites at baseline and 50
minutes post-IV fructose challenge, as a function of
the level of fructose consumption, are depicted in
Table 2. When compared to baseline ATP levels,
patients with high fructose consumption had signifi-
cant declines in a-ATP and a trend toward a decline in
b-ATP post-IV fructose challenge (P ¼ 0.002 and
0.06, respectively). In contrast, a-ATP and b-ATP did
not decline significantly from baseline in low-fructose
consumers after the acute fructose challenge (P ¼ 0.56
and 0.1, respectively). There was a significant differ-
ence between high- and low-fructose consumers
after the acute fructose challenge occurred in a-ATP
(P ¼ 0.05).
The relationships among changes in
metabolites at baseline and 50 minutes after IV fruc-
tose challenge and the presence or absence of hyperuri-
cemia are depicted in Table 3. Patients with hyperuri-
cemia had a trend toward a decline in a-ATP,
compared to patients without baseline hyperuricemia
(P ¼ 0.06). The median decline in b-ATP/Pi ratio
Fig. 2. Response to IV fructose challenge, by UA level.
Table 2.
P MRS Metabolites at Baseline and 50 Minutes Post-IV Fructose, by Fructose Intake
High Fructose
(15 g/day)
(N ¼ 9)
P Value D Baseline-50 Minutes
in High-Fructose Consumers
Low Fructose
(<15 g/day)
(N ¼ 7)
P Value D Baseline-5 0 Minutes
in Low-Fructose Consumers
P Value D Baseline-50
Minutes in High- Versus
Low-Fructose Consumers
a-ATP/total Pi
Baseline 0.30 (0.02) 0.24 (0.02)
Nadir 0.17 (0.03) 0.17 (0.02)
50 minutes 0.22 (0.01) 0.21 (0.02)
Absolute change 0.08 (0.02) 0.002 0.03 (0.02) 0.1 0.05
Percent change 24.52 (5.3) 11.87 (5.8) 0.13
b-ATP/total Pi
Baseline 12.5 (0.7) 13.2 (0.7)
Nadir 6.4 (3.5) 7.6 (2.9)
50 minutes 10.2 (1.0) 12.2 (1.3)
Absolute change 2.3 (1.1) 0.06 1.0 (1.6) 0.56 0.48
Percent change 17.3 (8.5) 5.3 (13.1) 0.44
c-ATP/total Pi
Baseline 0.13 (0.01) 0.15 (0.004)
Nadir 0.05 (0.02) 0.06 (0.2)
50 minutes 0.09 (0.01) 0.09 (0.01)
Absolute change 0.03 (0.01) 0.05 0.06 (0.007) <0.001 0.06
Percent change 22.61 (10.24) 40.03 (3.8) 0.14
PME/total Pi
Baseline 0.11 ( 0.01) 0.12 (0.01)
Nadir 0.11 (0.01) 0.09 (0.04)
50 minutes 0.18 (0.01) 0.16 (0.02)
Absolute change 0.06 (0.02) 0.01 0.04 (0.01) 0.03 0.37
Percent change 80.86 (29.32) 40.70 (19.39) 0.30
PDE/total Pi
Baseline 0.18 (0.01) 0.15 (0.01)
Nadir 0.12 (0.03) 0.11 (0.04)
50 minutes 0.14 (0.02) 0.13 (0.02)
Absolute change 0.04 (0.02) 0.08 0.02 (0.02) 0.32 0.57
Percent change 20.13 (8.81) 11.75 (11.01) 0.56
Page 5
was lower at nearly all time points (5-50 minutes) after
IV fructose challenge in patients with, compared to
those without, baseline hyperuricemia (Fig. 3). A stat-
istically significant greater nadir was noted in patients
with NAFLD versus without NAFLD (7.15 versus
4.58; P ¼ 0.03). No association between hepatic ATP
levels and alanine aminotransferase (ALT), BMI, or
alcohol consumption was observed.
Our study shows that fructose intake triggers tran-
sient declines in hepatic P
, a-ATP, b-ATP, and c-ATP,
findings consistent with hepatic ATP utilization during
the initial phases of fructose metabolism. Interestingly,
individuals with obesity and T2DM who habitually
consumed increased dietary fructose were more suscep-
tible to hepatic a-ATP and c-ATP depletion after an
acute IV fructose bolus than similar patients who con-
sumed less dietary fructose. Thus, fructose provides a
metabolic perturbation to the liver that can be utilized
to characterize interindividual differences in hepatic
energy homeostasis as well as variability in disease se-
verity and progression among patients with NAFLD.
We speculate that the association between habitual
consumption of high-fructose diets and susceptibility
to hepatic ATP depletion after an acute fructose chal-
lenge may reflect, at least in part, a compensatory up-
regulation of fructose-metabolizing enzymes in high-
fructose consumers. Hydrolysis of ATP during fructose
metabolism generates ADP and AMP. The latter is
either rephosphorylated by AMPK to regenerate ATP
Table 3.
P MRS Metabolites at Baseline and 50 Minutes Post-IV Fructose, by UA Levels
Increased UA
(5.5 mg/dL)
(N ¼ 8)
P Value D Baseline- 50
Minutes Increased UA
Normal UA
(<5.5 mg/dL)
(N ¼ 17)
P Value D Baseline-5 0
Minutes Normal UA
P Value Mean D Baseline-50
Minutes High Versus Normal
a-ATP/total Pi
Baseline 0.3 (0.02) 0.3 (0.01)
Nadir 0.15 (0.03) 0.17 (0.03)
50 minutes 0.2 (0.03) 0.2 (0.01)
Absolute change 0.1 (0.02) 0.004 0.04 (0.01) 0.003 0.06
Percent change 28.9 (6.2) 14.3 (4.2) 0.06
b-ATP/total Pi
Baseline 13.9 (1.5) 13.3 (0.5)
Nadir 4.5 (2.3) 7.1 (2.8)
50 minutes 10.92 (1.4) 10.9 (0.7)
Absolute change 2.9 (1.4) 0.07 2.4 (0.9) 0.02 0.76
Percent change 18.5 (9.4) 16.2 (7.2) 0.85
c-ATP/total Pi
Baseline 0.14 (0.01) 0.14 (0.01)
Nadir 0.04 (0.02) 0.06 (0.02)
50 minutes 0.08 (0.01) 0.09 (0.01)
Absolute change 0.06 (0.01) <0.001 0.05 (0.01) <0.001 0.47
Percent change 43.4 (5.8) 32.9 (6.4) 0.31
PME/total Pi
Baseline 0.15 (0.01) 0.11 (0.01)
Nadir 0.09 (0.03) 0.11 (0.02)
50 minutes 0.15 (0.01) 0.19 (0.01)
Absolute change 0.003 (0.02) 0.86 0.07 (0.01) <0.001 0.005
Percent change 9.91 (15.8) 81.8 (20.3) 0.03
PDE/total Pi
Baseline 0.15 (0.01) 0.18 (0.01)
Nadir 0.13 (0.03) 0.11 (0.04)
50 minutes 0.15 (0.01) 0.14 (0.01)
Absolute change 0.0003 (0.01) 0.97 0.04 (0.01) 0.0094 0.09
Percent change 3.7 (9.1) 19.5 ( 6.1) 0.04
Fig. 3. Median (interquartile range) changes after IV fructose, by
UA status.
HEPATOLOGY, Vol. 56, No. 3, 2012 ABDELMALEK ET AL. 957
Page 6
or further degraded to adenosine and, ultimately, UA.
UA tends to accumulate when the rate of ATP hydro-
lysis outstrips its regeneration. Thus, it is particularly
interesting that hyperuricemic subjects had lower base-
line a-ATP/P
as well as a greater absolute and percent
change from baseline in a-ATP, b-ATP, and c-ATP
after IV fructose challenge than those with normal
serum UA levels. Together, these data suggest that
habitual consumption of high-fructose–containing
diets provides a metabolic challenge that may impair
hepatic energy homeostasis in patients with underlying
insulin resistance (IR). Furthermore, increased serum
UA may serve as a surrogate serologic marker identify-
ing individuals who are unable to replenish liver ATP
stores effectively.
The decrease in absolute levels of hepatic ATP in vi-
ral and alcoholic hepatitis
and obesity
been interpreted as energy deficit’ or impaired ‘‘ATP
homeostasis.’ Humans with IR and hepatic steatosis
also have decreased hepatocellular ATP.
Even in met-
abolically well-controlled T2DM, hepatic energy me-
tabolism could be impaired when compared to age-
and BMI-matched and young lean controls.
uals with T2DM had 26% and 23% lower c-ATP
(1.68 6 0.11, 2.26 6 0.20, and 2.20 6 0.09 mmol/
L; P < 0.05) than age- and BMI-matched controls
and young healthy individuals, respectively. Further-
more, they had 28% and 31% lower Pi than did indi-
viduals from the matched control and young healthy
control groups (0.96 6 0.06, 1.33 6 0.13, and 1.41
6 0.07 mmol/L; P < 0.05). Even after adjustment for
hepatic lipid volume fraction, hepatic ATP and Pi
related negatively to hepatic insulin sensitivity (r ¼
0.665, P ¼ 0.010; r ¼0.680, P ¼ 0.007), but
not to whole body insulin sensitivity. These data sug-
gest that impaired hepatic energy metabolism and IR
could precede the development of steatosis in individu-
als with T2DM.
Likewise, it is conceivable that mitochondrial ATP
synthesis might also be decreased in prediabetic patients
with NAFLD. In support of this contention, patients
with nonalcoholic steatohepatitis exhibit alternations
and/or abnormalities of their mitochrondria.
Impaired energy homeostasis could also result from he-
patocellular c-ATP depletion resulting from increased
ATP utilization by energy-demanding processes, such as
adenosine triphosphatases, lipogenesis, or glu-
coneogenesis. Although loss of functional hepatocytes
resulting from necrosis and replacement with fat and
collagen may serve as yet another explanation for he-
patic c-ATP depletion, our study group of subjects with
obesity and T2DM lacked overt clinical or laboratory
evidence of liver damage. In such subjects, a dietary his-
tory of increased fructose consumption correlated with
reduced hepatic content of ATP, suggesting that the me-
tabolism of fructose may provide a previously unsus-
pected threat to hepatic energy homeostasis.
An alternative explanation may reflect the impaired
ATP generation in response to fructose ingestion that
is unique to fructose metabolism. As discussed above,
fructose is known to induce transient ATP depletion as
a result of its rapid phosphorylation.
The scavenger
enzyme, AMP deaminase 2, reclaims additional phos-
phates from ADP and, in the process, generates the
waste product, UA. Of note, AMPK is the master reg-
ulator of cellular energy flux in the liver. Under nor-
mal physiologic conditions, increased cellular content
of AMP activates AMPK and results in the prompt
regeneration of ATP. However, under conditions where
AMP kinase activity is low (as may occur in the setting
of IR), AMP is deaminated and increased production
of UA (as opposed to ATP) is favored. Fructose is also
known to up-regulate both its main transporter (i.e.,
Glut5) and its major enzyme (i.e., fructokinase).
Both fructokinase protein and activity in murine hepa-
tocytes increase after incubation with fructose.
thermore, laboratory rats fed diets high in fructose
show an increase in Glut5 in the intestinal epithelium
and an increase in fructokinase in their liver, compared
to controls.
Likewise, subjects with NAFLD and
higher intake of fructose have higher levels of fructoki-
nase mRNA in their liver biopsies, compared to con-
trol subjects with liver disease.
Humans given a high-
fructose diet show a more marked increase in UA in
response to fructose.
These studies suggest that the
effects of fructose to up-regulate its enzymes could
lead to a greater ATP depletion and hyperuricemia in
response to fructose. In turn, a more severe ATP
depletion could be a mechanism for potentiating cell
injury in subjects with NAFLD.
Elevated UA predicted both the baseline and nadir
of ATP depletion. This finding, which may be
explained by a tight link between the generation of
UA and ATP depletion in response to fructose admin-
istration, suggests that UA may be a biomarker of
fructokinase activity levels. The higher UA increase
induced by fructose in patients with cirrhosis therefore
appears to be a good marker of the diseased liver’s
inability to efficiently resynthesize ATP from its break-
down products.
Alternatively, the habitual consump-
tion of fructose may not allow for the efficient resyn-
thesis of ATP. Regardless, these data could provide an
explanation for why an elevated UA level may be a
predictor for NAFLD. However, we did not find UA
Page 7
as a predictor for more advanced liver disease in our
recent study, whereas the amount of fructose intake
did correlate with hepatic fibrosis.
Clearly, further
studies are needed to better understand the role of UA
in NAFLD and the progression of liver disease.
Our study has some limitations. First, our study was
an observational, cross-sectional study without a true
control population and no randomized intervention
designed to affect the endpoints. Second, histology was
unavailable for analysis, becqause liver biopsies are not
considered ethical in subjects without any evidence of
liver disease. Third, this study was not powered to assess
clinically significant differences between groups. Despite
this limitation, interesting insights regarding the poten-
tial mechanism(s) that may underlie fructose-related
liver injury were gained. Fourth, our study population
consisted of patients with known T2DM who had al-
ready received nutritional counseling. Thus, total fruc-
tose and caloric intake were lower in our study popula-
tion than might have been observed in a general
population. Despite this, the striking finding was that
we were still able to show a difference in hepatic ATP
and baseline and after IV fructose challenge in subjects
who consumed more fructose. Further, despite this low
threshold for defining fructose consumption, differences
in UA levels also correlated with the severity of ATP
depletion observed in response to fructose.
In conclusion, patients with obesity and T2DM with
increased habitual dietary fructose consumption show
reduced hepatic ATP concentrations, compared to those
with minimal dietary fructose intake. These data sup-
port our hypothesis that increased dietary fructose con-
sumption may impair hepatocellular energy homeostasis
and thus could be a risk factor for progressive liver
injury. Furthermore, hyperuricemia may serve as a sur-
rogate marker of hepatic ATP depletion after exposure
to fructose in patients with IR and, potentially,
NAFLD. The presence of hyperuricemia in patients
with IR may help clinicians to identify patients at risk
for cellular injury from fructose and hence may high-
light subjects at risk for progression of NAFLD.
Impaired hepatic energy homeostasis attributable to
increased dietary fructose consumption underscores the
urgent, dire need for increased public awareness of the
risks associated with high-fructose consumption.
The Fatty Liver Subgroup of the Look AHEAD Research Group
includes Jeanne M. Clark, M.D., M.P.H. (PI), Charalett Diggs,
R.N. (PC), Anna Mae Diehl, M.D. (former PI; now at Duke Uni-
versity, Durham, NC), Frederick L. Brancati, M.D., M.H.S., Ste-
phen Crawford, Ph.D., Susanne Bonekamp, Ph.D., D.V.M., Alena
Horska, Ph.D., Mariana Lazo, M.D., Ph.D., Sc.M., and Steven
Solga, M.D., from Johns Hopkins University (Baltimore, MD).
1. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis
to cirrhosis. H
EPATOLOGY 2006;43:S99-S112.
2. Bray GA, Nielsen SJ, Popkin BM. Consumption of high-fructose corn
syrup in beverages may play a role in the epidemic of obesity. Am J
Clin Nutr 2004;79:537-543.
3. Vos MB Kimmons JE, Gillespie C, Welsh J, Blanck HM. Dietary fructose
consumption among US children and adults: the Third National Health
and Nutrition Examination Survey. Medscape J Med 2008;10:160.
4. Putnam J, Allshouse JE. Food Consumption, Prices and Expenditures,
1970-1997. USDA Statistical Bulletin 965. Washington, DC: Food
and Rural Economics Division, Economics Research Service, US
Department of Agriculture; 1999.
5. French SA, Lin BH, Guthrie JF. National trends in soft drink con-
sumption among children and adolescents age 6 to 17 years: preva-
lence, amounts, and sources, 1977/1978 to 1994/1998. J Am Diet
Assoc 2003;103:1326-1331.
6. Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM,
et al. Fructose consumption as a risk factor for non-alcoholic fatty liver
disease. J Hepatol 2008;48:993-999.
7. Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O,
et al. A causal role for uric acid in fructose-induced metabolic syn-
drome. Am J Physiol Renal Physiol 2006;290:F625-F631.
8. Perez-Pozo SE, Schold J, Nakagawa T, Sanchez-Lozada LG, Johnson
RJ, Lillo JL. Excessive fructose intake induces the features of metabolic
syndrome in healthy adult men: role of uric acid in the hypertensive
response. Int J Obes (Lond) 2010;34:454-461.
9. Sanchez-Lozada LG, Mu W, Roncal C, Sautin YY, Abdelmalek M,
Reungjui S, et al. Comparison of free fructose and glucose to sucrose
in the ability to cause fatty liver. Eur J Nutr 2010;49:1-9.
10. Ackerman Z, Oron-Herman M, Grozovski M, Rosenthal T, Pappo O,
Link G, Sela BA. Fructose-induced fatty liver disease: hepatic effects of
blood pressure and plasma triglyceride reduction. Hypertension 2005;
11. Stanhope KL, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham
JL, et al. Consuming fructose-sweetened, not glucose-sweetened, bever-
ages increases visceral adiposity and lipids and decreases insulin sensitiv-
ity in overweight/obese humans. J Clin Invest 2009;119:1322-1334.
12. Schulze MB, Manson JE, Ludwig DS, Colditz GA, Stampfer MJ, Wil-
lett WC, Hu FB. Sugar-sweetened beverages, weight gain, and inci-
dence of type 2 diabetes in young and middle-aged women. JAMA
13. Cave M, Deaciuc I, Mendez C, Song Z, Joshi-Barve S, Barve S,
McClain C. Nonalcoholic fatty liver disease: predisposing factors and
the role of nutrition. J Nutr Biochem 2007;18:184-195.
14. Abdelmalek MF, Suzuki A, Guy C, Unalp-Arida A, Colvin R, Johnson
RJ, Diehl AM. Increased fructose consumption is associated with fibro-
sis severity in patients with nonalcoholic fatty liver disease. H
15. van den Berghe G, Bronfman M, Vanneste R, Hers HG. The mecha-
nism of adenosine triphosphate depletion in the liver after a load of
fructose. A kinetic study of liver adenylate deaminase. Biochem J 1977;
16. Cirillo P, Gersch MS, Mu W, Scherer PM, Kim KM, Gesualdo L,
et al. Ketohexokinase-dependent metabolism of fructose induces proin-
flammatory mediators in proximal tubular cells. J Am Soc Nephrol
17. Glushakova O, Kosugi T, Roncal C, Mu W, Heinig M, Cirillo P, et al.
Fructose induces the inflammatory molecule ICAM-1 in endothelial
cells. J Am Soc Nephrol 2008;19:1712-1720.
18. Cortez-Pinto H, Chatham J, Chacko VP, Arnold C, Rashid A, Diehl
AM. Alterations in liver ATP homeostasis in human nonalcoholic stea-
tohepatitis: a pilot study. JAMA 1999;282:1659-1664.
HEPATOLOGY, Vol. 56, No. 3, 2012 ABDELMALEK ET AL. 959
Page 8
19. Nair S, P Chacko V, Arnold C, Diehl AM. Hepatic ATP reserve and
efficiency of replenishing: comparison between obese and nonobese
normal individuals. Am J Gastroenterol 2003;98:466-470.
20. Bode JC, Zelder O, Rumpelt HJ, Wittkamp U. Depletion of liver
adenosine phosphates and metabolic effects of intravenous infusion of
fructose or sorbitol in man and in the rat. Eur J Clin Invest 1973;3:
21. Parks EJ, Skokan LE, Timlin MT, Dingfelder CS. Dietary sugars stim-
ulate fatty acid synthesis in adults. J Nutr 2008;138:1039-1046.
22. Rashid A, Wu TC, Huang CC, Chen CH, Lin HZ, Yang SQ, et al.
Mitochondrial proteins that regulate apoptosis and necrosis are induced
in mouse fatty liver. H
EPATOLOGY 1999;29:1131-1138.
23. Aguirre V, Uchida T, Yenush L, Davis R, White MF. The c-Jun
NH(2)-terminal kinase promotes insulin resistance during association
with insulin receptor substrate-1 and phosphorylation of Ser(307).
J Biol Chem 2000;275:9047-9054.
24. Chavin KD, Yang S, Lin HZ, Chatham J, Chacko VP, Hoek JB, et al.
Obesity induces expression of uncoupling protein-2 in hepatocytes and
promotes liver ATP depletion. J Biol Chem 1999;274:5692-5700.
25. Johnson RJ, Perez-Pozo SE, Sautin YY, Manitius J, Sanchez-Lozada
LG, Feig DI, et al. Hypothesis: could excessive fructose intake and uric
acid cause type 2 diabetes? Endocr Rev 2009;30:96-116.
26. Stirpe F, Della Corte E, Bonetti E, Abbondanza A, Abbati A, De Ste-
fano F. Fructose-induced hyperuricaemia. Lancet 1970;2:1310-1311.
27. Li Y, Xu C, Yu C, Xu L, Miao M. Association of serum uric acid level
with non-alcoholic fatty liver disease: a cross-sectional study. J Hepatol
28. Petta S, Camma C, Cabibi D, Di Marco V, Craxi A. Hyperuricemia is
associated with histological liver damage in patients with non-alcoholic
fatty liver disease. Aliment Pharmacol Ther 2011;34:757-766.
29. Afzali A, Weiss NS, Boyko EJ, Ioannou GN. Association between se-
rum uric acid level and chronic liver disease in the United States. H
30. Korieh A, Crouzoulon G. Dietary regulation of fructose metabolism in
the intestine and in the liver of the rat. Duration of the effects of a
high fructose diet after the return to the standard diet. Arch Int Physiol
Biochim Biophys 1991;99:455-460.
31. Ryan DH, Espeland MA, Foster GD, Haffner SM, Hubbard VS, John-
son KC, et al. Look AHEAD (Action for Health in Diabetes): design
and methods for a clinical trial of weight loss for the prevention of car-
diovascular disease in type 2 diabetes. Control Clin Trials 2003;24:
32. Skinner HA, Sheu WJ. Reliability of alcohol use indices. The Lifetime
Drinking History and the MAST. J Stud Alcohol 1982;43:1157-1170.
33. Vitolins MZ, Anderson AM, Delahanty L, Raynor H, Miller GD,
Mobley C, et al. Action for Health in Diabetes (Look AHEAD) trial:
baseline evaluation of selected nutrients and food group intake. J Am
Diet Assoc 2009;109:1367-1375.
34. Solga SF, Horska A, Hemker S, Crawford S, Diggs C, Diehl AM, et al.
Hepatic fat and adenosine triphosphate measurement in overweight
and obese adults using 1H and 31P magnetic resonance spectroscopy.
Liver Int 2008;28:675-681.
35. Gabr RE, Ouwerkerk R, Bottomley PA. Quantifying in vivo MR spec-
tra with circles. J Magn Reson 2006;179:152-163.
36. Chmelik M, Schmid AI, Gruber S, Szendroedi J, Krssak M, Trattnig S,
et al. Three-dimensional high-resolution magnetic resonance spectro-
scopic imaging for absolute quantification of 31P metabolites in human
liver. Magn Reson Med 2008;60:796-802.
37. Gallis JL, Delmas-Beauvieux MC, Biran M, Rousse N, Durand T,
Canioni P. Is cellular integrity responsible for the partial NMR invisi-
bility of ATP in isolated ischemic rat liver? NMR Biomed 1991;4:
38. Meyerhoff DJ, Boska MD, Thomas AM, Weiner MW. Alcoholic liver
disease: quantitative image-guided P-31 MR spectroscopy. Radiology
39. Rajanayagam V, Lee RR, Ackerman Z, Bradley WG, Ross BD. Quanti-
tative P-31 MR spectroscopy of the liver in alcoholic cirrhosis. J Magn
Reson Imaging 1992;2:183-190.
40. Szendroedi J, Chmelik M, Schmid AI, Nowotny P, Brehm A, Krssak
M, et al. Abnormal hepatic energy homeostasis in type 2 diabetes. H
41. Caldwell SH, de Freitas LA, Park SH, Moreno ML, Redick JA, Davis
CA, et al. Intramitochondrial crystalline inclusions in nonalcoholic stea-
tohepatitis. H
EPATOLOGY 2009;49:1888-1895.
42. Van den Berghe G. Fructose: metabolism and short-term effects on car-
bohydrate and purine metabolic pathways. Prog Biochem Pharmacol
43. Budillon G, Citarella C, Loguercio C, Nardone G, Sicolo P, Del Vec-
chio Blanco C. Hyperuricemia induced by fructose load in liver cirrho-
sis. Ital J Gastroenterol 1992;24:373-377.
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    • "Additionally, it may be relevant for understanding the potential adverse effects of fructose-rich diets. This is because ATP depletion impairs protein synthesis and induces inflammatory and prooxidative changes and thus, in a fructose-rich diet, this depletion might result in increased susceptibility of hepatocytes to injury leading to adverse hepatic conditions such as nonalcoholic fatty liver disease [62]. Furthermore, HepatoDyn has countless applications that go beyond studying the effects of fructose. "
    [Show abstract] [Hide abstract] ABSTRACT: The liver performs many essential metabolic functions, which can be studied using computational models of hepatocytes. Here we present HepatoDyn, a highly detailed dynamic model of hepatocyte metabolism. HepatoDyn includes a large metabolic network, highly detailed kinetic laws, and is capable of dynamically simulating the redox and energy metabolism of hepatocytes. Furthermore, the model was coupled to the module for isotopic label propagation of the software package IsoDyn, allowing HepatoDyn to integrate data derived from 13C based experiments. As an example of dynamical simulations applied to hepatocytes, we studied the effects of high fructose concentrations on hepatocyte metabolism by integrating data from experiments in which rat hepatocytes were incubated with 20 mM glucose supplemented with either 3 mM or 20 mM fructose. These experiments showed that glycogen accumulation was significantly lower in hepatocytes incubated with medium supplemented with 20 mM fructose than in hepatocytes incubated with medium supplemented with 3 mM fructose. Through the integration of extracellular fluxes and 13C enrichment measurements, HepatoDyn predicted that this phenomenon can be attributed to a depletion of cytosolic ATP and phosphate induced by high fructose concentrations in the medium.
    Full-text · Article · Apr 2016
    • "31 P magnetic resonance spectroscopy (MRS) has proven to be a useful clinical and diagnostic tool to measure hepatic high-energy phosphates and other phosphorus-containing compounds in vivo (hereafter, " phosphorus metabolites " ). Alterations in phosphorus metabolites have been seen in various diseases such as cirrhosis123 , non-alcoholic fatty liver disease [4, 5], viral hepatitis [6, 7] and diabetes mellitus8910. Levels of these 31 P MRS detected phosphorus metabolites can be quantified as relative metabolite resonanceamplitude ratios (hereafter, " metabolite ratios " ) or as absolute concentrations. Absolute quantification is desirable since metabolite ratios are susceptible to complications due to simultaneous changes in metabolite content with disease. "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose: Absolute concentrations of high-energy phosphorus (31P) metabolites in liver provide more important insight into physiologic status of liver disease compared to resonance integral ratios. A simple method for measuring absolute concentrations of 31P metabolites in human liver is described. The approach uses surface spoiling inhomogeneous magnetic field gradient to select signal from liver tissue. The technique avoids issues caused by respiratory motion, chemical shift dispersion associated with linear magnetic field gradients, and increased tissue heat deposition due to radiofrequency absorption, especially at high field strength. Methods: A method to localize signal from liver was demonstrated using superficial and highly non-uniform magnetic field gradients, which eliminate signal(s) from surface tissue(s) located between the liver and RF coil. A double standard method was implemented to determine absolute 31P metabolite concentrations in vivo. 8 healthy individuals were examined in a 3 T MR scanner. Results: Concentrations of metabolites measured in eight healthy individuals are: γ-adenosine triphosphate (ATP) = 2.44 ± 0.21 (mean ± sd) mmol/l of wet tissue volume, α-ATP = 3.2 ± 0.63 mmol/l, β-ATP = 2.98 ± 0.45 mmol/l, inorganic phosphates (Pi) = 1.87 ± 0.25 mmol/l, phosphodiesters (PDE) = 10.62 ± 2.20 mmol/l and phosphomonoesters (PME) = 2.12 ± 0.51 mmol/l. All are in good agreement with literature values. Conclusions: The technique offers robust and fast means to localize signal from liver tissue, allows absolute metabolite concentration determination, and avoids problems associated with constant field gradient (linear field variation) localization methods.
    Full-text · Article · Dec 2015
    • "We have found that fructose exposure drastically lowers cellular ATP content by 50%. Unlike hexokinase or glucokinase; fructokinase does not experience feedback inhibition by fructose- 1-phosphate, so unregulated fructokinase activity depletes ATP (Abdelmalek et al., 2012; Malaisse et al., 1989). Since mitoNEET is a 2Fe-2S transfer protein localized to the mitochondrial outer membrane, it is tempting to speculate that the up-regulation of mitoNEET expression is in response to fructose induced ATP depletion, resulting in an increased need for mitochondrial respiration that requires 2Fe-2S clusters in components of the mitochondrial respiratory chain. "
    [Show abstract] [Hide abstract] ABSTRACT: The past half-century has witnessed a dramatic increase in the incidence of obesity and diabetes (Jacobson, 2004; Krilanovich, 2004). Both of these occurrences have been accompanied by an increase in the consumption of fructose. Unlike glucose, the metabolism of fructose is not subject to negative feed-back inhibition and can impose stress on intracellular energy stores (Ishimoto et al., 2012; Lanaspa et al., 2014, 2012). In the present study we identify the ability of fructose to increase the sensitivity of pancreatic beta cells to TNFα induced cytotoxicity. Exposure of pancreatic beta cells to fructose induced fructokinase and glut-5 expression, two proteins critical for the metabolism of fructose. Importantly, the increased metabolism of fructose by beta cells was accompanied by an increase in the expression of mitoNEET. MitoNEET is a 2Fe-2S cluster binding protein localized to the outer mitochondrial membrane (Wiley et al., 2007a). The increased expression of mitoNEET mediated an enhanced sensitivity of the pancreatic beta cells to TNFα induced cytotoxicity that was prevented by suppression of mitoNEET expression or pharmacological inhibition of its ability to release its 2Fe-2S cluster.
    Article · Oct 2015
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