Bergamot Polyphenols Improve Dyslipidemia and Pathophysiological Features in a Mouse Model of Non-Alcoholic Fatty Liver Disease

Abstract

There is a need for continued drug development for nonalcoholic steatohepatitis (NASH). Bergamot is a plant whose fruit juice is enriched with flavonoids and phenolic compounds which improves dyslipidemia and markers of systemic inflammation in patients with Metabolic Syndrome. The aim of this study was to perform a preclinical "proof of concept" study of Bergamot polyphenolic formulation (BPF99) for the treatment of NASH. A disease reversal study was performed in the diet-induced animal model of NAFLD (DIAMOND). Groups of 8 weeks old mice were randomly assigned to receive chow diet, high fat diet with sugar in drinking water (Western diet-WD). Mice on WD were further randomized to continue on WD gavaged with vehicle or continue on WD with additional gavage of BPF99 (50 mg/ kg) after 16 weeks of diet. Mice were euthanized after 11 additional weeks. The primary endpoint was resolution of NASH. Secondary endpoints included changes in individual histological features, body weight, liver enzymes, dyslipidemia, markers of oxidative stress and molecular markers of disease activity and fibrosis. The results showed that BPF99 reduced ALT (mean 71.6 vs 44.6 IU/l, p < 0.01), triglycerides (38.8 vs 28.1 mg/dl, p < 0.05), LDL-C (39.2 vs 23.7 mg/dl, p < 0.001). It significantly improved nASH resolution (p < 0.001) and the SAF scores (p < 0.05) while the NAS improvement approached significance. BPF99 reduced markers of oxidative stress, along with reduced JNK and p38 MAP kinase activity. BPF99 did not reduce the number of mice with fibrosis but improved collagen proportional area (p < 0.04) and procollagen I and III expression. Collectively our results showed that BPF99 resolves NASH and ameliorates key histological and pathophysiological features of NASH along with improvement in ALT and dyslipidemia in the DIAMOND mice. Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity and mortality for which there are no approved therapies 1. The clinical-histological spectrum of NAFLD extends from a nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) 2. NASH is a more aggressive phenotype of NAFLD and is

Mikania micrantha Extract Inhibits HMG-CoA Reductase and ACAT2 and Ameliorates Hypercholesterolemia and Lipid Peroxidation in High Cholesterol-Fed Rats

“…Many previous studies have shown that plant polyphenols, flavonoids, carotenoids, vitamins can effectively lower the level of TC, TG, LDL and MDA in hyper-cholesterolemic rodents [ 36 , 37 , 38 , 39 ]. The present results were following the findings of Musolino et al [ 40 , 41 ] that demonstrated that bergamot polyphenolic fraction (BPF) prevented the alteration of lipid profile in hypercholesterolemic rats, counteracting oxidative stress markers and also ameliorate the dysregulation of the lipoprotein metabolism; suggesting that the richness of antioxidant properties may play an important role in improving dyslipidemia.…”

Quercitrin Ameliorates Hyperlipidemia and Hepatic Steatosis in Ovariectomized Mice

“…Flavonoids, commonly found in apples, grapes, onions, and herbs, exhibit potential beneficial effects on human health, including anti-allergic, antiviral, antioxidant, and anti-inflammatory activities, and they have been shown to have preventive and therapeutic effects against NAFLD [ 9 ]. Moreover, dietary flavonoid consumption improves dyslipidemia and decreases hepatic fat accumulation [ 10 , 11 ].…”

Pathophysiological Basis for Nutraceutical Supplementation in Heart Failure: A Comprehensive Review

“…Scientific evidence shown that bergamot polyphenolic fraction (BPF) improves serum lipemic profile and modulates blood pressure in patients with metabolic syndrome (MetS), a state which contribute to the development of HF [31,32,33]. Previous scientific evidence obtained with citrus fruits, shown their beneficial effects and clarify some mechanisms involved in MetS [34,35].…”

“…The hypolipemic effect of BPF seems to be related to the modulatory properties of naringin and neohesperidin. Indeed, dietary hesperetin inhibits hepatic t ri acylglycerol ( TG) accumulation, w h i c h m a y b e associated with the reduced activity of TG synthetic enzymes, such as phosphatidate phosphohydrolase [33]. In addition, in vitro studies showed that naringenin and hesperetin decrease the availability of lipids for assembly of apoB-containing lipoproteins.…”