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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

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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.
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, conrming 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, ve 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-
inammatory 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
Lindeld Cardiology, Lindeld, 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 signicantly enhanced
rosuvastatin-induced effect on serum lipemic prole compared to
rosuvastatin alone, an effect associated to signicant 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 Graeciaof 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 identied 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 ultrasonograc evidences of
NAFLD and at least three out of ve previous identied 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 signicant 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 signicant
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 proles 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
... 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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... 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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