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The Effect of Bergamot-Derived Polyphenolic Fraction on LDL Small Dense Particles and Non Alcoholic Fatty Liver Disease in Patients with Metabolic Syndrome

Authors:
Micaela Gliozzi
Micaela Gliozzi
Micaela Gliozzi
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Cristina Carresi at Magna Graecia University
Cristina Carresi
Vincenzo Musolino
Vincenzo Musolino
Ernesto Palma at Magna Graecia University
Ernesto Palma
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Abstract

The occurrence of Metabolic Syndrome (MS) represents an independent risk factor for developing cardiovascular disease states in patients suffering from type 2 diabetes mellitus. Moreover, both the size of LDL particles and liver dysfunction identified as non alcoholic fatty liver disease (NAFLD) represent important biomarkers for the development of cardiometabolic risk in patients with MS. Here we studied the effect of bergamot polyphenolic fraction (BPF) in patients with MS and NAFLD. 107 patients were enrolled at the San Raffaele IRCCS (Rome). All of them showed ultrasonografic evidences of NAFLD and at least three out of five previous identified criteria for the diagnosis of MS. Patients were divided into two groups: one receiving placebo and the second receiving BPF 650 mg twice a day for 120 consecutive days. In the group receiving BPF 650 mg twice a day, a significant reduction of fasting plasma glucose, serum LDL cholesterol and triglycerides alongside with an increase of HDL cholesterol was found. This effect was accompanied by significant reduction of both ultrasonographic and metabolic biomarkers of NAFLD. Moreover, a significant reduction of small dense LDL particles, as detected via proton NMR Spectroscopy, was found after BPF treatment. In conclusion, our data confirm the beneficial effect of bergamot-extract in patients with MS an effect highlighted by significant reduction of small dense LDL particles and by improvement of NAFLD biomarkers. This suggests a potential preventive role of bergamot derivatives in reducing cardiometabolic risk.
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blocking antibody. These data support that MR activation in human
endothelial cells promotes ICAM-1-mediated leukocyte-EC adhesion,
an important step in early atherosclerosis lesion formation. To further
explore the mechanisms for MR-mediated EC activation, we now
demonstrate that MR activation up-regulates VCAM-1 and E-selectin
mRNA expression (2 and 3.5 fold respectively), whereas P-selectin is
not regulated by MR. We also further explored the mechanism of MR-
mediated regulation of endothelial ICAM-1 expression. In transient
transfection experiments performed in HUVEC, we have shown that
aldosterone is able to activate (2 fold) a 3 Kb promoter region
upstream the transcription start site of human ICAM-1 gene. Co-
incubation with spironolactone was able to inhibit the effect of
aldosterone, confirming the presence of elements responsive to
signaling pathway(s) activated by MR. In order to localize and
characterize MR responsive cis-element(s) and the corresponding
transcription factor(s) binding to this regulatory region, five 5′-
deletion constructs of ICAM-1 promoter were subcloned in a vector
upstream of the luciferase gene. Data of transcriptional activity
showed the presence of regulatory element(s) required for ICAM-1
expression via MR in the promoter region between nt-872 and -1141.
Bioinformatics analysis of this region revealed the presence of four
different highly conserved regulatory elements: three SP1 binding
sites, one NF-κB binding site, one AP1 binding site and one GRE/MRE.
The role of these transcription factors in MR-mediated regulation of
ICAM-1 expression was investigated using c-JUN and IKBαdominant
negative constructs. Blocking of either c-Jun or NF-κB pathway
resulted in a marked reduction of the aldosterone effect on ICAM-1
promoter activity, suggesting the involvement of these transcription
factors. These studies explore the molecular mechanism for the pro-
inflammatory effects of MR activation in the vasculature that may
contribute to explain the protective effects of MR antagonists in
clinical trials. Moreover to better understand the crosstalk between
MR activation and ICAM1 in the development of atherosclerosis
lesions, we developed a mouse model double KO for ApoE and ICAM1,
where we are currently studying the pro-atherogenic effects of
aldosterone.
doi:10.1016/j.ijcme.2015.05.013
Bergamot polyphenolic fraction potentiates rosuvastatin induced
effect on LDL-cholesterol, LOX-1 expression and protein kinase B
phosphorylation in patients with hyperlipidemia
M. Gliozzi
a,b,c
, V. Musolino
a,b,c
, C. Carresi
a,b,c
, F. Oppedisano
a,b
,
F. Casale
a,b
, M. Iannone
a,f
, C. Muscoli
a,b,c
, E. Palma
a,b
, S. Muscoli
d
,
A. Romeo
a,b
, F. Romeo
d
, R. Walker
e
, V. Mollace
a,b,c
a
Interregional Research Centre for Food Safety&Health,IRC-FSH,Catanzaro,
Italy
b
Dept. Health Sciences, University of Catanzaro Magna Graecia, Catanzaro,
Italy
c
IRCCS San Raffaele Pisana, Rome, Italy
d
Dept. of Cardiology, Tor Vergata University, Rome, Italy
e
Lindfield Cardiology, Lindfield, Sydney, NSW, Australia
f
ARPACal, Catanzaro, Italy
Statins are the most commonly prescribed drugs to treat lipid
disorders and reduce cardiometabolic risk. However, the use of
natural compounds may represent a valid support for statin-
intolerant patients. We aimed to assess the effect of bergamot-
derived polyphenolic fraction (BPF) in modulating serum cholesterol
and biomarkers of vascular oxidative stress in patients with mixed
hyperlipidemia either untreated or treated with rosuvastatin.
A prospective, open-label, parallel group, placebo-controlled
study on 77 patients with elevated serum LDL-C and triglycerides
was designed. Patients were randomly assigned to a control group
receiving placebo (n = 15), two groups receiving orally rosuvastatin
(10 and 20 mg/daily for 30 days n = 16 for each group), a group
receiving BPF alone orally (1000 mg/daily for 30 days; n = 15) and a
group receiving BPF (1000 mg/daily given orally) plus rosuvastatin
(10 mg/daily for 30 days; n = 15).
Both doses of rosuvastatin and BPF reduced total cholesterol, LDL-
C, the LDL-C/HDL-C ratio and urinary mevalonate in hyperlipidemic
patients, compared to control group. The cholesterol lowering effect
was accompanied by reductions of malondialdehyde, oxyLDL recep-
tor LOX-1 and phosphoPKB, which are all biomarkers of oxidative
vascular damage, in peripheral polymorphonuclear cells.
Addition of BPF to rosuvastatin significantly enhanced
rosuvastatin-induced effect on serum lipemic profile compared to
rosuvastatin alone, an effect associated to significant reductions of
biomarkers used for detecting oxidative vascular damage, suggesting
a multiaction synergistic potential for BPF in statin-taking patients.
BPF may be an alternative therapeutic strategy for hyperlipidemia in
patients with statin-induced side effects.
doi:10.1016/j.ijcme.2015.05.014
The effect of bergamot-derived polyphenolic fraction on LDL
small dense particles and non-alcoholic fatty liver disease in
patients with metabolic syndrome
J. Ehrlich
a,c
, M. Gliozzi
a,b
, C. Carresi
a
, V. Musolino
a
, E. Palma
a
,
C. Muscoli
a,b
, C. Vitale
b
, G. Muscianisi
a
, E. Janda
a
, S. Ragusa
a
,
R. Mollace
a
, R. Walker
a
, V. Mollace
a,b
a
Interregional Research Centre for Food Safety & Health, Department of
Health Sciences, University “Magna Graecia”of Catanzaro, Catanzaro,
Italy
b
San Raffaele IRCCS, Rome, Italy
c
University of Rome “Tor Vergata”, Rome, Italy
The occurrence of Metabolic Syndrome (MS) represents an
independent risk factor for developing cardiovascular disease states
in patients suffering from type 2 diabetes mellitus. Moreover, both
the size of LDL particles and liver dysfunction identified as non-
alcoholic fatty liver disease (NAFLD) represent important biomarkers
for the development of cardiometabolic risk in patients with MS. We
studied the effect of bergamot polyphenolic fraction (BPF) in patients
with MS and NAFLD. 107 patients were enrolled at the San Raffaele
IRCCS (Rome). All of them showed ultrasonografic evidences of
NAFLD and at least three out of five previous identified criteria for
the diagnosis of MS. Patients were divided into two groups: one
receiving placebo and the second receiving BPF 650 mg twice a day
for 120 consecutive days. In the group receiving BPF 650 mg twice a
day, a significant reduction of fasting plasma glucose, serum LDL
cholesterol and triglycerides alongside with an increase of HDL
cholesterol was found. This effect was accompanied by a significant
reduction of both ultrasonographic and metabolic biomarkers of
NAFLD as well as by a decrease of small dense LDL particles.
Overall, our data show that bergamot-deriving polyphenolic
fraction given in patients with MS and NAFLD, leads to concomitant
amelioration of the lipemic and glycemic serum profiles and to
substantial reduction of liver steatosis. This effect, alongside with a
reduction of pro-atherogenic small dense LDL and enhancement of
anti-atherogenic high dense HDL, shed new light on the potential use
of bergamot-extract for reducing cardiometabolic risk in patients
with MS.
doi:10.1016/j.ijcme.2015.05.015
Abstracts 7

Supplementary resource (1)

ABC 2014033113210154-2
Data
December 2015
Micaela Gliozzi · Cristina Carresi · Vincenzo Musolino · Ernesto Palma · Vincenzo Mollace
... In a follow-up study involving 15 patients treated with SGAs [21], a higher dose of BPF (1000 mg/day for 30 days) resulted in a 1.6% reduction in body weight (p = 0.004) and a trend of BMI reduction (p = 0.005), although no significant changes in other metabolic parameters were observed [21]. Gliozzi et al. (2014) [22] conducted an RCT with 107 patients with metabolic syndrome and NAFLD, administering 650 mg of BPF twice daily for 120 days. The study reported significant reductions in fasting plasma glucose by 17% (p < 0.05), LDL cholesterol by 37.7% (p < 0.05), triglycerides by 31% (p < 0.05), and an increase in HDL cholesterol by 28.9% (p < 0.05). ...
... In a follow-up study involving 15 patients treated with SGAs [21], a higher dose of BPF (1000 mg/day for 30 days) resulted in a 1.6% reduction in body weight (p = 0.004) and a trend of BMI reduction (p = 0.005), although no significant changes in other metabolic parameters were observed [21]. Gliozzi et al. (2014) [22] conducted an RCT with 107 patients with metabolic syndrome and NAFLD, administering 650 mg of BPF twice daily for 120 days. The study reported significant reductions in fasting plasma glucose by 17% (p < 0.05), LDL cholesterol by 37.7% (p < 0.05), triglycerides by 31% (p < 0.05), and an increase in HDL cholesterol by 28.9% (p < 0.05). ...
... Markers of hepatic steatosis, including ALT, AST, and γ-GT, also significantly decreased. Although there were no significant changes in body weight or visceral fat, BPF demonstrated notable improvements in lipid profiles and liver function [22]. ...
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... In particular BPF, an enriched polyphenolic formulation obtained from the juice and albedo of bergamot, has protective activities in the management of atherosclerosis, metabolic disorders, and cardiotoxicity due to its antioxidant, anti-inflammatory, and lipidlowering effects [54][55][56][57]. Furthermore, BPF reduces serum cholesterol and triglyceride levels, improving systemic inflammation and endothelial function [58][59][60][61]. Interesting experimental data also demonstrate the beneficial protective action of BPF in preventing hyperglycemia [62,63]. ...
... [61,62] showed important protective activities in the management of atherosclerosis, metabolic disorders, and cardiotoxicity, mainly due to its antioxidative, anti-inflammatory, and lipid-lowering effects [54][55][56][57]. In fact, clinical studies carried out on animal and cellular models showed that BPF has hypolipemic and antiatherogenic effects by interfering with the autophagic pathway and preventing pathogenic lipid accumulation [59,149,150]. In addition, BPF possesses powerful antioxidant effects, decreases lipid peroxidation biomarkers, and prevents ROS accumulation in different cell types [58][59][60]. ...
... In fact, clinical studies carried out on animal and cellular models showed that BPF has hypolipemic and antiatherogenic effects by interfering with the autophagic pathway and preventing pathogenic lipid accumulation [59,149,150]. In addition, BPF possesses powerful antioxidant effects, decreases lipid peroxidation biomarkers, and prevents ROS accumulation in different cell types [58][59][60]. BPF also improves the activity of endogenous antioxidant enzymes, including superoxide dismutase, glutathione peroxidase, and glutathione S transferase P1 [61]. Indeed, a recent double-blind study conducted on 60 patients with Type 2 diabetes mellitus and hyperlipemia identified interesting beneficial effects of BPF. ...
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... In recent years, evidence has been collected that Citrus bergamia Risso & Poiteau (bergamot), a Citrus species rich in flavonoids, may represent a potential source of natural antioxidants able to counteract HFD-induced alteration of lipidaemic profile both in animal models of hyperlipidaemia and in patients [40,41]. Moreover, a polyphenolic-rich extract derived from bergamot juice has been found to improve lipoprotein profiles in patients with liver steatosis alongside having a beneficial effect on liver function [42]. Finally, bergamot fibres alone or in combination with natural polyphenolic extracts were found to be able to antagonize fat accumulation and insulinaemic response both in animals and obese patients, suggesting that dietary supplementation with such products may have a beneficial response in metabolic regulation under HFD conditions [43,44]. ...
... Plasma lipoprotein particles were detected as previously described [42] by means of the proton NMR spectroscopy technique with the simultaneous concentration measure of lipoprotein subclasses of different sizes. NMR provides calculated values for mean very-low-density lipoprotein (VLDL), LDL and HDL particle sizes plus estimates of total and VLDL, TGs and HDL cholesterol. ...
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... In terms of nutrition, citrus trees are considered to produce fruits with high nutritional value: fruit pulp contains 6-12% sugar, the organic acid content ranges from 0.4-1.2%, vitamin C accounts for 40-90 mg/100 g of fresh fruit flesh (Nguyen Minh Hieu et al., 2013), and medicinally they can help improve the health of newly ill people and the elderly as polyphenol compounds help enhance liver function by reducing fat accumulation (Tripoli et al., 2007;Gliozzi et al., 2014). Furthermore, citrus fruit tree are the leader in Vietnam in terms of planted area and their export potential is very large. ...
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... The neutralization of free radical overproduction is further reflected by the amelioration of the oxidative status of the LDL profile detected in patients with metabolic syndrome. Particularly, BPF administration determined a significant re-arrangement of lipoproteins with a reduction in oxidated LDL small-size atherogenic particles and an increase in large-size antiatherogenic HDL [107]. In addition, in BPF-treated patients, a significant reduction in serum total cholesterol (TC) and LDL-C, probably due to the inhibition of HMG-CoA reductase and triglycerides (TG), was detected. ...
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... The addition of bergamot to rosuvastatin therapy enhanced its effects (152 ± 5 mg/dL and 200 ± 4 mg/dL, respectively vs. 235 ± 5 mg/dL). The second study (Gliozzi et al. [136]) analyzed 107 patients with MetS and NAFLD (nonalcoholic fatty liver disease). Divided into 2 groups, half received placebo, the other half 650 mg of bergamot twice a day. ...
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  • MINERVA MED
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Article
  • Mar 2021
Nghiên cứu biến động quần thể cá dảnh (Puntioplites proctozystron) ở Búng Bình Thiên nhằm xác định sự biến động kích cỡ và số lượng, xác định các tham số tăng trưởng làm cơ sở cho việc khai thác và quản lý nguồn lợi thủy sản. Nghiên cứu tại Búng Bình Thiên từ tháng 7/2018-6/2019 với 12 đợt thu mẫu tương ứng 12 tháng. Ngư cụ là dớn, lưới, đăng, chài, mắt lưới từ 0,5 cm đến 4,5 cm, nhằm thu cá ở các kích cỡ và các tầng nước khác nhau trong búng. Mẫu cá được cân (g/cá thể) và đo chiều dài tổng (cm). Kết quả thu được 1.975 cá thể với nhiều kích cỡ khác nhau trong cùng 1 thời điểm, trong đó cá cỡ nhỏ chiếm tỷ lệ cao trong mùa mưa và mùa lũ, trong khi cá kích cỡ lớn chiếm tỷ lệ cao trong mùa khô tháng 3-7. Số liệu được xử lý bằng phần mềm FISAT II. Kết quả cho thấy có 2 đợt bổ sung quần là tháng 1-2 và tháng 9 do cá đẻ trong BBT kết hợp cá từ nước lũ thượng nguồn. Cá thể thu được có chiều dài tổng lớn nhất là 23 cm vào tháng 5, trong khi chiều dài tối đa của loài cá này có thể đạt được là L∞=30 cm, hệ số tăng trưởng K=1,5/năm, mức chết tự nhiên M=1,5/năm, mức chết do khai thác F=0,8/năm, to=0,1, số lượng cá thể có kích cỡ lớn (18-23cm) có rất ít trong BBT, không bắt gặp cá dài hơn 23,5 cm.
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The antidote effect of Quinone Oxidoreductase 2 (QR2) inhibitor on paraquat-induced toxicity in vitro and in vivo.
Article
Full-text available
BACKGROUND AND PURPOSE The mechanisms of paraquat (PQ)-induced toxicity are poorly understood and PQ poisoning is often fatal due to a lack of effective antidotes. In this study we report the effects of N-[2-(2-methoxy-6H-dipyrido{2,3-a:3,2-e}pyrrolizin-11-yl)ethyl]-2-furamide (NMDPEF), a melatonin-related inhibitor of quinone oxidoreductase2 (QR2) on the toxicity of PQ in vitro & in vivo. EXPERIMENTAL APPROACH Prevention of PQ-induced toxicity was tested in different cells, including primary pneumocytes and astroglial U373 cells. Cell death and reactive oxygen species (ROS) were analysed by flow cytometry and fluorescent probes. QR2 silencing was achieved by lentiviral shRNAs. PQ (30 mg·kg−1) and NMDPEF were administered i.p. to Wistar rats and animals were monitored for 28 days. PQ toxicity in the substantia nigra (SN) was tested by a localized microinfusion and electrocorticography. QR2 activity was measured by fluorimetry of N-benzyldihydronicotinamide oxidation. KEY RESULTS NMDPEF potently antagonized non-apoptotic PQ-induced cell death, ROS generation and inhibited cellular QR2 activity. In contrast, the cytoprotective effect of melatonin and apocynin was limited and transient compared with NMDPEF. Silencing of QR2 attenuated PQ-induced cell death and reduced the efficacy of NMDPEF. Significantly, NMDPEF (4.5 mg·kg−1) potently antagonized PQ-induced systemic toxicity and animal mortality. Microinfusion of NMDPEF into SN prevented severe behavioural and electrocortical effects of PQ which correlated with inhibition of malondialdehyde accumulation in cells and tissues. CONCLUSIONS AND IMPLICATIONS NMDPEF protected against PQ-induced toxicity in vitro and in vivo, suggesting a key role for QR2 in the regulation of oxidative stress. LINKED ARTICLE This article is commented on by Baltazar et al., pp. 44–45 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02017.x
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Mortality from Coronary Heart Disease in Subjects with Type 2 Diabetes and in Nondiabetic Subjects with and without Prior Myocardial Infarction
Article
Full-text available
  • Jul 1998
Type 2 (non-insulin-dependent) diabetes is associated with a marked increase in the risk of coronary heart disease. It has been debated whether patients with diabetes who have not had myocardial infarctions should be treated as aggressively for cardiovascular risk factors as patients who have had myocardial infarctions. To address this issue, we compared the seven-year incidence of myocardial infarction (fatal and nonfatal) among 1373 nondiabetic subjects with the incidence among 1059 diabetic subjects, all from a Finnish population-based study. The seven-year incidence rates of myocardial infarction in nondiabetic subjects with and without prior myocardial infarction at base line were 18.8 percent and 3.5 percent, respectively (P<0.001). The seven-year incidence rates of myocardial infarction in diabetic subjects with and without prior myocardial infarction at base line were 45.0 percent and 20.2 percent, respectively (P<0.001). The hazard ratio for death from coronary heart disease for diabetic subjects without prior myocardial infarction as compared with nondiabetic subjects with prior myocardial infarction was not significantly different from 1.0 (hazard ratio, 1.4; 95 percent confidence interval, 0.7 to 2.6) after adjustment for age and sex, suggesting similar risks of infarction in the two groups. After further adjustment for total cholesterol, hypertension, and smoking, this hazard ratio remained close to 1.0 (hazard ratio, 1.2; 95 percent confidence interval, 0.6 to 2.4). Our data suggest that diabetic patients without previous myocardial infarction have as high a risk of myocardial infarction as nondiabetic patients with previous myocardial infarction. These data provide a rationale for treating cardiovascular risk factors in diabetic patients as aggressively as in nondiabetic patients with prior myocardial infarction.
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Association between microsomal triglyceride transfer protein gene polymorphism and the biological features of liver steatosis in patients with Type II diabetes
Article
Full-text available
  • Sep 2000
Non-alcoholic steatohepatitis is frequent in Type II (non-insulin-dependent) diabetes mellitus and can lead to fibrosis and cirrhosis. The interindividual variability in the occurrence of nonalcoholic steatohepatitis suggests, however, a genetic modulation. Microsomal triglyceride transfer protein (MTP) is necessary for the assembly and secretion of VLDL and when the protein is not functional, such as in abetalipoproteinaemia, a steatohepatitis occurs. We therefore assessed the association between a functional polymorphism in the promoter region of MTP gene (-493 G/T) and the biological features of steatohepatitis in Type II diabetic patients. We studied 271 patients with Type II diabetes. Determination of -493 G/T polymorphism was made by PCR-RFLP. Increased liver enzymes were used as surrogates of liver steatosis and alanine aminotransferase concentration was the outcome variable for the multivariate analysis. Liver ultrasonography was available for a subgroup of patients with newly diagnosed diabetes. The proportion of patients with increased alanine aminotransferase was higher in GG than in GT and TT subgroups (23%, 11% and 6%, respectively, p = 0.01). Additionally, patients with high alanine aminotransferase concentrations were more likely to be young (p = 0.01), male (p = 0.001), obese (p = 0.04) and have low HDL-cholesterol (p = 0.01). In multivariate analysis, the MTP genotype was independently associated with alanine aminotransferase concentration (p = 0.0023) as well as sex and body mass index but not HDL-cholesterol. The -493 G/T MTP gene polymorphism is associated with biological surrogates of steatohepatitis in patients with Type II diabetes. The G allele which is responsible for a decrease in MTP gene transcription is prone to increase the intrahepatic triglycerides content, conferring by this a genetic susceptibility for steatohepatitis.
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Residual Cardiovascular Risk Despite Optimal LDL Cholesterol Reduction with Statins: The Evidence, Etiology, and Therapeutic Challenges
Article
  • Nov 2011
  • Curr Atherosclerosis Rep
This review captures the existence, cause, and treatment challenges of residual cardiovascular risk (CVR) after aggressive low-density lipoprotein cholesterol (LDL-C) reduction. Scientific evidence implicates low high-density lipoprotein cholesterol (HDL-C) and high triglycerides (TG) in the CVR observed after LDL-C lowering. However, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial with fenofibrate, the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) study with torcetrapib, and the recently terminated Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study with niacin, do not clearly attribute risk reduction value to HDL-C/TG modulation. The optimum approach to long-term lipid-modifying therapies for CVR reduction remains uncertain. Consequently, absolute risk modulation via lifestyle changes remains the centerpiece of a strategy addressing the physiologic drivers of CVR associated with HDL-C/TG, especially in the context of diabetes/metabolic syndrome.
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Small, dense low-density lipoproteins (LDL) are predictors of cardio- and cerebro-vascular events in subjects with the metabolic syndrome
Article
  • Sep 2008
  • CLIN ENDOCRINOL
Small, dense low-density lipoproteins (LDL) are a feature of the metabolic syndrome (MS) but their predictive role still remains to be established. We performed a 2-year follow-up study in 124 subjects with MS (63 +/- 6 years), as defined by the American Heart Association/National Heart, Lung and Blood Institute guidelines, to assess clinical and biochemical predictors of cerebro- and cardio-vascular events. Beyond traditional cardiovascular risk factors, we measured LDL size and subclasses by gradient gel electrophoresis. Clinical events were registered in the 25% of subjects. At univariate analysis subjects with events had increased prevalence of elevated fasting glucose (P = 0.0117), smoking (P = 0.0015), family history of coronary artery disease (P = 0.0033) and higher levels of total- and LDL-cholesterol (P = 0.0027 and P = 0.0023, respectively); LDL size was lower (P < 0.0001), due to reduced larger subclasses and increased small, dense LDL (all P < 0.0001). At multivariate analysis the following were independent predictors of events (univariate odd ratios were calculated): low HDL-cholesterol (OR 15.4, P = 0.0238), elevated fasting glucose (OR 12.1, P = 0.0102), elevated small, dense LDL (OR 11.7, P = 0.0004), elevated blood pressure (OR 9.2, P = 0.0392), smoking (OR 4.8, P = 0.0054). This is the first study that assessed the predictive role of small, dense LDL beyond traditional cardiovascular risk factors in subjects with MS.
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Effect of hesperetin, a citrus flavonoid, on the liver triacylglycerol content and phosphatidate phosphohydrolase activity in orotic acid-fed rats
Article
  • Feb 2001
The effect of dietary hesperetin on the hepatic lipid content and the enzyme activities involved in triacylglycerol (TG) synthesis in rats fed diets with or without 1% orotic acid (OA) was studied. Hepatic TG content was raised by approximately 5-fold after administration of OA for 10 days. The OA-feeding significantly increased the activity of hepatic microsomal phosphatidate phosphohydrolase (PAP), which is the rate-limiting enzyme for TG synthesis. Hepatic glucose-6-phosphate dehydrogenase (G6PDH) and malic enzyme activities were also increased. An addition of 1% hesperetin to the OA-supplemented diet resulted in the decrease of the hepatic TG content by 44% and of microsomal PAP activity. Dietary hesperetin alone neither affected liver TG content nor PAP activity significantly. OA-feeding caused an increased liver cholesterol level, whereas simultaneous addition of hesperetin and OA reduced its content to the control level. A slight reduction of hepatic cholesterol by hesperetin was also observed in the OA-free dietary group. The present study demonstrated that dietary hesperetin can reduce the hepatic TG accumulation induced by OA, and this was associated with the reduced activity of TG synthetic enzyme, PAP.
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NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome
Article
  • Mar 2002
Nonalcoholic steatohepatitis (NASH) is often linked with disorders that are clearly associated with insulin resistance (IR): obesity, type 2 diabetes mellitus, and hypertriglyceridemia. We tested the hypotheses that (1) IR is an essential requirement for the development of NASH and (2) a high association between IR and liver disease is relatively specific for NASH. We measured body mass index (BMI), waist/hip ratio, and fasting serum lipid, insulin, C-peptide, and glucose levels in 66 patients with NASH (21 with advanced fibrosis and 45 with mild fibrosis). IR was determined by the homeostasis model assessment (HOMA). We also determined the strength of the association of NASH with insulin resistance syndrome (IRS) as defined by World Health Organization criteria. To assess whether the finding of IR was relatively specific to NASH rather than simply to obesity or liver disease, we compared the results of a subset of 36 patients with less-severe NASH with 36 age- and sex-matched patients with chronic hepatitis C virus (HCV) of comparable fibrotic severity. IR was confirmed in 65 patients (98%) with NASH, and 55 (87%) fulfilled minimum criteria for IRS. IR was found in lean as well as in overweight and obese patients. The IR values and the prevalence of IRS (75% vs. 8.3%) were significantly higher in those with NASH than in comparable cases of HCV. Hyperinsulinemia was attributable to increased insulin secretion rather than decreased hepatic extraction. In conclusion, most patients with NASH have IRS, and there is a near-universal association between NASH and IR irrespective of obesity. IR is present in mild as well as advanced cases of NASH but is unusual in chronic HCV of similar fibrotic severity.
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The hypocholesterolemic effect of lemon peels, lemon pectin, and the waste stream material of lemon peels in hybrid F1B hamsters
Article
  • Mar 2002
We found in preliminary studies with hamsters that citrus peels have a cholesterol lowering effect comparable to that of pectin extracted from these peels. We wanted to examine whether the cholesterol lowering effect of the peels could be completely accounted for by the pectin in the peels. We fed cholesterol enriched (0.1 %,w/w) semipurified diets containing 3% (w/w) of cellulose, lemon peels, lemon pectin, and the waste stream material of the lemon peels to hybrid F1B hamsters for a period of 8 weeks. The waste stream of the lemon peels is the left over after extraction of the lemon pectin. Feeding the semipurified diets resulted in an increase of plasma cholesterol levels in all the dietary groups after 2 and 4 weeks on the diets. Cholesterol concentrations in the cellulose fed hamsters continued to increase after 4 weeks on the diet, whereas cholesterol levels in the other groups had reached a plateau. As a consequence, the plasma cholesterol levels in the hamsters fed the peels (5.59 +/- 0.74 mmol/L, mean +/- SD, n = 14), pectin (5.19 +/- 0.48 mmol/L), or waste stream (5.53 +/- 0.94 mmol/L) were lower than those in the hamsters fed cellulose (6.71 +/- 1.52 mmol/L) after 8 weeks on the diets. Differences in total plasma cholesterol were reflected in differences in both VLDL and LDL cholesterol concentration, but this effect was more distinct for the VLDL. There was no effect of the type of fiber on HDL cholesterol levels. Liver cholesterol concentrations paralleled. the concentrations of plasma cholesterol and the liver cholesterol concentrations in the hamsters fed the peels (3.57+/- 1.01 micromol/g liver, mean +/- SD, n = 14), pectin (4.86 +/- 1.42), and the waste stream (4.96 +/- 1.89) were lower than those in the cellulose group (7.19 +/- 2.32). The hamsters fed the peels, pectin, or waste stream tended to have a higher excretion of fecal bile acids and neutral sterols then the cellulose fed hamsters. The results of this study suggest that lemon peels and the waste stream of the lemon peels are as effective in lowering plasma and liver cholesterol in hamsters as the pectin extracted from the peels and that also compounds other than pectin are probably responsible for the cholesterol lowering effect of the citrus peels.
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Hypolipidemic Effects of Citrus bergamia Risso et Poiteau Juice in Rats Fed a Hypercholesterolemic Diet
Article
  • Jan 2008
Citrus bergamia Risso et Poiteau fruits have been traditionally utilized, in Calabria (Italy), as a popular remedy for their hypolipidemic properties. C. bergamia juice total phenol content (2474.35+/-38 microg/mL) was evaluated by the Folin-Ciocalteu method; moreover, HPLC analysis led to the identification of naringin (520 ppm), neoeriocitrin (370 ppm), and neohesperidin (310 ppm). The present study was designed to investigate the hypolipidemic effects of C. bergamia juice and its protective effect on liver of hyperlipidemic rats. Chronic administration of C. bergamia (1 mL/rat/day) provoked a significant reduction in serum cholesterol, triglycerides, and low-density lipoprotein (LDL) levels and an increase in high-density lipoprotein (HDL) levels; moreover, histopathological observations showed, in rats submitted to C. bergamia treatment, a protection of hepatic parenchyma. In addition, fecal neutral sterols and fecal bile acid excretion was found to be increased after C. bergamia treatment. These results suggest that the hypocholesterolemic effect of C. bergamia may be mediated by the increase in fecal neutral sterols and total bile acids excretion. In addition to the hypolipidemic effect, the juice shows radical scavenging activity in the diphenylpicrylhydrazyl (DPPH) test; probably the two effects are related. These observations suggest that the positive intake of C. bergamia may reduce the risk of some cardiovascular diseases through its radical scavenging function and hypocholesterolemic action.
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