Short-term weight loss and hepatic triglyceride reduction: evidence of
a metabolic advantage with dietary carbohydrate restriction1–3
Jeffrey D Browning, Jonathan A Baker, Thomas Rogers, Jeannie Davis, Santhosh Satapati, and Shawn C Burgess
Background: Individuals with nonalcoholic fatty liver disease
(NAFLD) have excess intrahepatic triglycerides. This is due, in part,
to increased hepatic synthesis of fat from carbohydrates via lipo-
genesis. Although weight loss is currently recommended to treat
NAFLD, little attention has been given to dietary carbohydrate re-
Objective: The aim of this study was to determine the effectiveness
of 2 wk of dietary carbohydrate and calorie restriction at reducing
hepatic triglycerides in subjects with NAFLD.
Design: Eighteen NAFLD subjects (n = 5 men and 13 women) with
a mean (6SD) age of 45 6 12 y and a body mass index (in kg/m2)
of 35 6 7 consumed a carbohydrate-restricted (,20 g/d) or calorie-
restricted (1200–1500 kcal/d) diet for 2 wk. Hepatic triglycerides
were measured before and after intervention by magnetic resonance
Results: Mean (6SD) weight loss was similar between the groups
(24.0 6 1.5 kg in the calorie-restricted group and 24.6 6 1.5 kg in
the carbohydrate-restricted group; P = 0.363). Liver triglycerides
decreased significantly with weight loss (P , 0.001) but decreased
significantly more (P = 0.008) in carbohydrate-restricted subjects
(255 6 14%) than in calorie-restricted subjects (228 6 23%).
Dietary fat (r = 0.643, P = 0.004), carbohydrate (r = 20.606, P =
0.008), posttreatment plasma ketones (r = 0.755, P = 0.006), and
respiratory quotient (r = 20.797, P , 0.001) were related to a re-
duction in liver triglycerides. Plasma aspartate, but not alanine,
aminotransferase decreased significantly with weight loss (P ,
Conclusions: Two weeks of dietary intervention (’4.3% weight
loss) reduced hepatic triglycerides by ’42% in subjects with
NAFLD; however, reductions were significantly greater with dietary
carbohydrate restriction than with calorie restriction. This may have
been due, in part, to enhanced hepatic and whole-body oxidation.
This trial was registered at clinicaltrials.gov as NCT01262326.
Am J Clin Nutr doi: 10.3945/ajcn.110.007674.
A major sequela of insulin resistance and obesity is non-
alcoholic fatty liver disease (NAFLD), a spectrum of pathology
ranging from simple triglyceride accumulation in hepatocytes to
cirrhosis (1). An astounding one-third of adults in a major urban
center are affected by NAFLD and, if this prevalence is reflective
of the nation as a whole, .71 million individuals have excess
liver fat in the United States (2).
Data from rodent models suggest that a complex interplay
between processes of lipid accrual (lipogenesis, lipolysis, and
diet) and disposal (lipoprotein secretion and fatty acid oxida-
tion) contribute to the deposition of triglycerides in liver. Im-
portantly, hepatic de novo lipogenesis, a process that converts
dietary carbohydrate into fat in the postprandial state, was
recently documented to be constitutively active in humans
with NAFLD (3, 4). Increased fatty acid synthesis generates
malonyl-CoA, an intermediate that has been shown to inhibit
carnitine palmitoyl transferase-1, the protein responsible for the
transport of long-chain fatty acids into mitochondria where they
undergo b-oxidation (5–7). These data led us to hypothesize
that dietary carbohydrate restriction would be effective at re-
ducing hepatic triglyceride content in NAFLD by limiting the
accrual of hepatic lipids via lipogenesis and simultaneously
enhancing their disposal via mitochondrial b-oxidation. In-
deed, we previously applied this dietary approach in a single
case study and showed a marked decline in hepatic triglyceride
content after 5 wk, despite the requisite increase in dietary fat
intake (8). However, whether dietary carbohydrate restriction
was more effective than the currently recommended low-
calorie, low-fat diet for the reduction of hepatic triglyceride
was not addressed.
Thepresentstudy wasdesignedtobuildonourpriorreport and
compare the effectiveness of carbohydrate and calorie restriction
at reducing hepatic triglyceride content in individuals with he-
patic steatosis after a similar degree of weight loss. The primary
endpoint of the study was the change in hepatic triglyceride
1From the Departments of Internal Medicine (JDB), Pathology (JAB and
TR), and Pharmacology (SCB), The Advanced Imaging Research Center
(JDB, JD, SS, and SCB), The University of Texas Southwestern Medical
Center at Dallas, Dallas, TX.
2Supported by the Clinical and Translational Science Award at The Univer-
sity of Texas Southwestern (UL1RR024982), the Task Force for Obesity Re-
search (TORS) at The University of Texas Southwestern (5UL1DE019584), the
TORS Human Biology Core (5PL1DK081183), the TORS Molecular and
Metabolic Mouse Phenotyping Core (5PL1DK081182), and NIH grants
5RL1DK081187 (to JDB and SCB), 1K23DK074396 (to JDB), RR02584 (to
SCB), R01DK078184 (to SCB), and DK082872 (to TR).
3Address reprint requests and correspondence to JD Browning, Depart-
ment of Internal Medicine, Division of Digestive and Liver Diseases and the
Advanced Imaging Research Center, 5323 Harry Hines Boulevard, Dallas,
TX 75390-8568. E-mail: firstname.lastname@example.org.
Received November 4, 2010. Accepted for publication February 14, 2011.
Am J Clin Nutr doi: 10.3945/ajcn.110.007674. Printed in USA. ? 2011 American Society for Nutrition
1 of 5
AJCN. First published ahead of print March 2, 2011 as doi: 10.3945/ajcn.110.007674.
Copyright (C) 2011 by the American Society for Nutrition
content after 2 wk of dietary intervention, as determined by
proton magnetic resonance spectroscopy (1H-MRS).
SUBJECTS AND METHODS
Eighteen consecutive patients who were evaluated by a single
hepatologist (JDB) at The University of Texas Southwestern
All subjects had a negative viral hepatitis serologies, transferrin
saturation ,40%, normal a1-antitrypsin and ceruloplasmin con-
centrations, negative autoimmune liver disease markers (nuclear
antibody, mitochondrial antibody, smooth muscle antibody, liver-
kidney microsomal antibody), and no history of medication use
associated with hepatic steatosis. On the basis of an interview with
the treating physician, all subjects either abstained from alcohol or
consumed ,5 alcoholic beverages annually. Liver biopsy samples
were obtained from 14 of 18 subjects as part of their clinical
evaluation. None of the subjects were cirrhotic or had laboratory or
radiographic evidence of portal hypertension. All subjects had
stable weight in the 6 mo preceding enrollment, and none were
actively engaged in a weight-loss program.
The protocol and consent form were approved by the In-
stitutional Review Board of The University of Texas South-
western Medical Center, and all participants provided written
informed consent before enrollment.
At enrollment, all subjects underwent1H-MRS to determine
liver triglyceride content and were assigned to either a low-car-
bohydrate or low-calorie diet in a semirandom manner to achieve
equivalence between groups. Before the diet was initiated, all
subjects underwent a teaching session with the Clinical and
Translational Research Center (CTRC) dietitian. After complet-
ing the 2-wk dietary intervention, the subjects underwent a repeat
1H-MRS for the measurement of liver triglyceride content and
had their respiratory quotient measured with a Delta Trak II in-
direct calorimeter (Sensormedics, Yorba Linda, CA).
limit carbohydrate intake to ,20 g/d (9). They initiated this diet
on their own for the first 7 d of the study, keeping a detailed
dietary record. This was done to increase compliance and to add
heterogeneity by allowing the subjects to individualize their diet
with respect to protein and fat intake. Food for the final 7 d was
provided to subjects as frozen meals prepared by the CTRC
kitchen in accordance with the energy intake and food prefer-
ences documented in the dietary record.
Subjects assigned to a low-calorie diet were asked to continue
their regular diet for 4 d before the study and to record their food
intake. On the basis of this dietary record, the CTRC kitchen
prepared all meals for the 14 d of the study in accordance with the
dietary composition and food preferences recorded by the indi-
viduals, but reduced in energy to ’1200 kcal/d for women and to
’1500 kcal/d for men following current recommendations for the
treatment of NAFLD (10).
Blood was collected into heparin-treated tubes and centrifuged
immediately to isolate plasma from red blood cells. Plasma
glucose, cholesterol, triglyceride, HDL cholesterol, and amino-
transferases were measured by using a Vitros 250 spectropho-
tometric analyzer (Ortho-Clinical Diagnostics, Rochester, NY).
A commercially available enzyme-linked immunosorbent assay
kit was used to measure insulin (Millipore, Billerica, MA). Other
routine chemistry values were determined by a commercial
laboratory (Quest Diagnostics, Madison, NJ).
Localized1H-NMR spectra of the liver were acquired while the
subjects were in the supine position by using a 1.5-T Gyroscan
Intera MR system (Philips Medical Systems, Amsterdam, Neth-
erlands) as previously described (11). Sagittal, coronal, and axial
slices through the right lobe of the liver were acquired, and a
27-cm3volume of interest was positioned, avoiding major blood
vessels, intrahepatic bile ducts, and the lateral margins of the liver.
After the system was tuned and shimmed, spectra were collected
by using a Q-body coil for radiofrequency transmission and signal
reception and a double-echo PRESS sequence with interpulse
delay (Tr = 3 s) and echo time (Te = 25 ms). The hepatic tri-
glyceride content is expressed as a percentage of the methylene
resonance referenced to the combined signal from both methylene
groups and water (12, 13). Resonance areas were determined by
using the 1-D NMR processor in ACD/Laboratories 9.0 (Ad-
vanced Chemistry Development, Toronto, Canada).
Statistical analyses were performed by using SigmaPlot
11.0 (Systat Software Inc, Chicago, IL). Differences between
the 2 groups were evaluated by using unpaired t tests (means)
or Mann-Whitney rank sums tests (medians). Differences be-
tween 2 repeated measures were analyzed by using the paired
t test. Proportions were evaluated with Fisher’s exact test.
Comparison of repeated measures between groups was per-
formed by using 2-factor repeated-measures analysis of vari-
ance. Correlations between variables were determined by using
the Spearman rank-sum test. Statistical significance was set
at P , 0.05.
The study consisted of 18 subjects who were equally divided
between carbohydrate or calorie restriction. Subjects tended to be
middle-aged and were primarily female (Table 1). The 2 dietary
groups were matched with regard to age, sex, weight, and body
mass index (BMI; in kg/m2). Fasting lipid profiles were also
similar. Serum aminotransferase concentrations were similarly
elevated in both treatment groups, as was fasting plasma glu-
cose. The hepatic triglyceride content was elevated in all sub-
jects (.5.6%) (11), with a similar degree of elevation in both
All subjects completed their assigned diet and experienced
weight loss (24.3 6 1.4 kg; P , 0.001). Despite differences in
macronutrient composition (Table 2), weight loss was similar
between the low-carbohydrate and low-calorie groups (Table 1).
Plasma alanine aminotransferase (ALT) and fasting glucose
2 of 5
BROWNING ET AL
concentrations did not change significantly in either group,
whereas plasma triglycerides and aspartate aminotransferase
(AST) fell after 2 wk of weight loss. Plasma ketones were sig-
nificantly higher (469 6 171 compared with 1164 6 548, P =
0.016) and respiratory quotients were significantly lower (0.89 6
0.07 compared with 0.78 6 0.04, P , 0.001) in the low-carbo-
hydrate group. Posttreatment plasma insulin concentrations were
similar between the groups (P = 0.191).
Aside from a single low-calorie subject, hepatic triglyceride
content decreased in both groups (absolute reduction: 29 6 8%,
P , 0.001; relative reduction: 242 6 23%, P , 0.001). Despite
comparable overall weight loss, however, the decrease in hepatic
triglyceride content was greater in the low-carbohydrate than in
the low-calorie group (Table 1).
No significant relation was observed between the degree of
weight loss and the proportion of protein, fat, or carbohydrate in
both dietary fat and carbohydrate intake and the magnitude of
reduction in hepatic triglyceride content (r = 0.643, P = 0.004;
r = 20.606, P = 0.008, respectively). No relation between
changes in hepatic triglycerides during weight loss and the
proportion of dietary protein was apparent (P = 0.378). The
magnitude of reduction in liver triglycerides was also highly
correlated with posttreatment plasma total ketone concentration
and respiratory quotient (r = 0.755, P = 0.006, and r = 20.797,
P , 0.001, respectively). Other posttreatment metabolic varia-
bles, such as plasma concentrations of cholesterol, triglycerides,
glucose, insulin, and transaminases, showed no relation with
reduction in liver triglyceride content.
18 subjects with NAFLD by using1H-MRS before and 2 wk after
obtaining equal weight loss via 2 dietary interventions that dif-
fered in macronutrient composition. A major finding of this study
was that, regardless of dietary intervention, the intrahepatic tri-
after a ’4.3% weight loss over 2 wk. However, given a similar
degree of weight loss, the low-carbohydrate diet resulted in sig-
nificantly greater intrahepatic triglyceride reduction than did the
low-calorie diet (Table 1). The magnitude of liver triglyceride
Characteristics of subjects before and after weight loss1
Low-calorie diet (n = 9)Low-carbohydrate diet (n = 9)P value2
BeforeAfter BeforeAfterGroupTime Group · time
Sex ratio (F:M)
NAFLD activity score
Total cholesterol (mg/dL)
Fasting glucose (mg/dL)
Hepatic TG content (%)
47 6 123
42 6 11
4.3 6 1.8
1.3 6 1.4
34 6 9
5.8 6 1.6
0.8 6 0.9
36 6 4
33 6 9 35 6 4
96 6 21
207 6 29
154 6 65
56 6 28
77 6 49
0.8 6 0.2
122 6 55
92 6 20
96 6 1
204 6 53
115 6 46
15 6 4
81 6 45
0.2 6 0.1
106 6 21
97 6 14
212 6 34
215 6 90
50 6 18
80 6 51
0.7 6 0.2
113 6 34
92 6 15
95 6 1
175 6 24
103 6 34
17 6 2
98 6 25
0.2 6 0.1
87 6 14
19 6 10
14 6 7
72 6 23
22 6 13
10 6 7
45 6 14
1ALT, alanine aminotransferase; AST, aspartate aminotransferase; NAFLD, nonalcoholic fatty liver disease; TG, triglyceride.
2Analysis by 2-factor repeated-measures ANOVA unless otherwise indicated.
3Mean 6 SD (all such values).
4Unpaired t test.
5Fisher’s exact test.
Characteristics of diets1
diet (n = 9)
diet (n = 9)P value2
Energy intake (kcal/d)
Fat intake (%)
1325 6 1801553 6 5170.229
16 6 3
34 6 6
50 6 4
53 6 12
49 6 9
169 6 33
33 6 4
59 6 7
8 6 5
121 6 34
105 6 44
26 6 8
42 6 8
37 6 2
18 6 7
37 6 4
38 6 6
15 6 4
1All values are means 6 SDs.
2Analyisis by unpaired t test.
CARBOHYDRATE AND CALORIE RESTRICTION IN NAFLD
3 of 5
with the proportion of carbohydrate and fat in the diet, which in-
dicated that macronutrient composition is an independent de-
period of negative energy balance. Indeed, the observed relation
between both plasma ketones and respiratory quotient suggests
that the fate of hepatic triglycerides during dietary weight loss is
oxidative disposal—a process that occurs to a greater degree
during carbohydrate restriction.
Regardless of dietary macronutrient composition, weight loss
effectively reduced liver fat. However, our results indicate that
there is a metabolic advantage to dietary carbohydrate restriction
for the short-term reduction of liver triglyceride content. This
advantage appears to be related to enhanced lipid oxidation
mandated by reduced carbohydrate intake (14). Both calorie and
concentrations,consistent withenhanced ketogenesisand hepatic
mitochondrial b-oxidation. However, ketone concentrations were
significantly higher in carbohydrate-restricted individuals. Like-
wise, whole-body lipid oxidation, as assessed by respiratory
quotient, was also significantly higher in the low-carbohydrate
group. Taken together, these data indicate that the reduction in
hepatic triglycerides observed after 2 wk of weight loss is asso-
ciated with enhanced hepatic and whole-body lipid oxidation and
that this enhancement occurred to a greater degree during carbo-
in hepatic mitochondrial oxidative capacity between subjects
with NAFLD and control subjects, whereas defects in oxidative
phosphorylation may be present in nonalcoholic steatohepatitis
to be higher in subjects with NAFLD and NASH (15), which
is indirect evidence of increased hepatic fatty acid oxidation.
However, an alternative interpretation could involve impaired
is also direct evidence that hepatic oxidation of long-chain fatty
acids is elevated in obese insulin-resistant individuals (21), but
similar studies in persons with NAFLD have not been performed.
The rapid reduction in liver triglycerides in the present study, in
association with enhanced lipid oxidation, suggests that mito-
chondrial oxidative capacity in NAFLD subjects is intact but
conditions. Such a rapid responsewould be unlikely in the setting
of an intrinsic defect in mitochondrial structure and function (16,
22). A harmonious explanation for this observation is substrate-
level inhibition of b-oxidation, possibly consequent to increased
hepatic de novo lipogenesis. This explanation is supported by the
strong inverse relation between the magnitude of hepatic tri-
glyceride reduction and dietary carbohydrate intake, perhaps be-
cause of the primary role of dietary carbohydrate in lipid
Since our initial report (8) and another report (23), it has been
unclear whether the effect of a low-carbohydrate diet on hepatic
triglycerides was specific to the diet or a more general feature of
weight loss. Although we have shown here a metabolic advan-
tage of carbohydrate restriction, the increased effectiveness of
this diet in reducing liver triglycerides cannot be extrapolated
beyond the 2-wk period of observation. The only other study
similar to ours was carried out by Kirk et al (24) in 22 subjects.
They showed that carbohydrate restriction reduced hepatic tri-
glycerides more than did calorie restriction after 48 h of negative
energy balance (22% weight); however, the 2 dietary inter-
ventions were equally effective by ’11 wk of negative energy
balance (27% weight). Most studies that have examined dietary
intervention in NAFLD have focused on calorie restriction, with
or without fitness training, and have typically lasted ?3 mo (10).
Within the surgical literature, several studies have examined
the effect of short-term calorie restriction (’500–800 kcal/d for
2–12 wk) on hepatic fat due to the operative difficulties en-
countered as a consequence of hepatomegaly and reduced in-
traabdominal space. Consistent with the dramatic reduction in
hepatic triglycerides in our study, 80% of the reduction in liver
volume occurred in the first 2 wk of calorie restriction and was
maximal by 8 wk (25). Likewise, the hepatic triglyceride content
was reduced by 40% after 4 wk and by 43% after 12 wk (25, 26).
Taken together, these data suggest that a pool of hepatic tri-
glycerides is rapidly mobilized during energy restriction, espe-
cially in the absence of dietary carbohydrate. The remainder
appears to be mobilized more slowly; gastric bypass patients
were shown to achieve postoperative reductions in hepatic tri-
glycerides of ’60% and ’90% only after 6 and 12 mo, re-
A surprising finding was that plasma ASTwas most responsive
to the reduction in hepatic triglycerides, decreasing 37 6 19 U/L
after 2 wk (P , 0.001). Conversely, despite the reduction in
liver fat, plasma ALT concentrations remained unchanged. Most
subjects (16 of 18) were followed clinically at an average fol-
low-up interval of 3.2 6 1.3 mo after study completion. Al-
though the posttreatment weight of the study population was
unchanged at follow-up (P = 0.149), plasma ALT concentrations
decreased significantly (from 88 6 34 to 33 6 16 U/L; P ,
0.001), with normalization in 79% of subjects. The reason for
this differential response of transaminases is unclear but may
be related to differences in enzyme half-life, enhanced sinu-
soidal clearance, changes in release from the cytosolic and/or
mitochondrial compartments, or changes in hepatic metabolic
activity (28, 29). However, the decline in AST may prove to be
clinically relevant to monitor the response during initial weight
reduction in subjects with NAFLD.
Interpretation of the present study results is subject to limi-
tations. This study was not designed to determine the therapeutic
efficacy of the diets in NAFLD. Rather, the primary goal was to
energy balance in the presence and near absence of dietary car-
not performed, precluding our ability to comment on histologic
referral bias because of the demographics of the study population
(primarily middle-aged women).
In conclusion, 2 wk of dietary intervention resulting in a re-
However, dietary carbohydrate restriction was significantly more
effective at reducing liver triglycerides than was calorie re-
striction. Our data suggest that this was due to enhanced lipid
disposal via hepatic and whole-body oxidation. Additionally, the
increase in lipid oxidation in these subjects suggests that mito-
chondrial oxidative capacity is attenuated in NAFLD during
weight-stable conditions. Of the serum transaminases, only AST
4 of 5
BROWNING ET AL
decreased in parallel with the reduction in liver triglycerides. Download full-text
Despite reductions in the liver triglyceride content, ranging from
30% to 50% in these subjects, improvements in serum ALT con-
centrations were not initially apparent.
We thank the staff of the CTRC at the University of Texas Southwestern
Medical Center and Jay D Horton for critical reading of the manuscript.
The authors’ responsibilities were as follows—JDB: designed and con-
ducted the research, analyzed the data, performed the statistical analysis,
wrote the manuscript, and had primary responsibility for the final content;
JAB: analyzed the data and provided the essential materials; TR: analyzed
the data, provided the essential materials, and wrote the manuscript; JD: con-
ducted the research; SS: analyzed the data and provided essential materials;
and SCB: designed the research, analyzed the data, provided the essential
materials, and wrote the manuscript. The authors had no conflicts of interest
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