Atorvastatin promotes AMPK signaling to protect against high fat diet‑induced non‑alcoholic fatty liver in golden hamsters

Abstract

Non-alcoholic fatty liver disease (NAFLD) is characterized by diffuse fatty acid degeneration and excess fat accumulation in the liver. Notably, the currently available medications used to treat NAFLD remain limited. The aim of the present study was to investigate the protective role of atorvastatin (Ato) against NAFLD in golden hamsters fed a high fat diet (HFD) and in HepG2 cells treated with palmitate, and identify the underlying molecular mechanism. Ato (3 mg/kg) was administered orally every day for 8 weeks to the hamsters during HFD administration. Hamsters in the model group developed hepatic steatosis with high serum levels of triglyceride, cholesterol, insulin and C-reactive protein, which were effectively reduced by treatment with Ato. Additionally, the relative liver weight of hamsters treated with Ato was markedly lower compared with that of the model group. Hematoxylin and eosin, and oil red O staining indicated that the livers of the animals in the model group exhibited large and numerous lipid droplets, which were markedly decreased after Ato treatment. Western blot analysis indicated that Ato inhibited fat accumulation in the liver through the AMP-activated protein kinase (AMPK)-dependent activation of peroxisome proliferator activated receptor α (PPARα), peroxisome proliferator-activated receptor-γ coactivator 1 α and their target genes. Furthermore, in vitro, Ato inhibited PA-induced lipid accumulation in HepG2 cells. This inhibitory effect was attenuated following Compound C treatment, indicating that AMPK may be a potential target of Ato. In conclusion, the increase in AMPK-mediated PPARα and its target genes may represent a novel molecular mechanism by which Ato prevents NAFLD.

Natural Piperine Improves Lipid Metabolic Profile of High-Fat Diet-Fed Mice by Upregulating SR-B1 and ABCG8 Transporters

“…Quantitative analysis showed that piperine at the concentrations of 50 or 100 μM markedly reduced the intracellular fat deposition by 36% (Figure C). The magnitude of piperine effect was similar to that induced by the positive control atorvastatin (10 μM), consistent with the report for reduction of the plasma levels of TC and LDL due to HMG-CoA reductase inhibition. , In addition, intracellular TG content was detected in HepG2 cells. As shown in Figure D, TG level was significantly increased upon FFA treatment.…”

Temporal Development of Dyslipidemia and Nonalcoholic Fatty Liver Disease (NAFLD) in Syrian Hamsters Fed a High-Fat, High-Fructose, High-Cholesterol Diet

“…In this study, both plasma concentrations of TG, LDL-cholesterol and HDL-cholesterol were increased in the NASH-fed hamster. While these observations are in agreement with other studies in high fat, high-fructose, high cholesterol diet-induced hamster models of dyslipidemia and hepatic steatosis [ 26 , 27 , 28 ], there are also studies showing no change in HDL-cholesterol in hamsters fed a diet containing fat, carbohydrates and cholesterol [ 29 , 30 ]. The dyslipidemia observed in human patients with NAFLD is typically characterized by increased plasma TG concentrations, increased or unchanged LDL-cholesterol and decreased HDL-cholesterol [ 31 ].…”

“…Recent studies in hamster models of NAFLD/NASH have reported that it is possible to induce most of the hallmarks of NASH in hamsters fed diets high in fat, with some combination of added carbohydrate and/or cholesterol during a shorter time span (12–25 weeks) [ 26 , 28 , 29 , 30 , 54 , 60 ]. In the study done by Briand and colleagues, hamsters were fed a free-choice diet (choice between chow and a high-fat diet (40.8 kcal% fat, 44.4 %kcal carbohydrate and 0.5% cholesterol) with 10% fructose in drinking water) for 12–25 weeks.…”

Targeting AMPK by Statins: A Potential Therapeutic Approach

“…Zhang et al reported that atorvastatin significantly inhibited NAFLD progression via AMPK signaling pathway promotion in the golden hamster model of fat diet-NAFLD. In addition, they showed that AMPK inhibition by compound C counteracted the inhibitory effect of atorvastatin on fat accumulation in the HepG2 cell line [ 63 ]. In another study, Kim and colleagues who evaluated the effects of fluvastatin on cholesterol hemostasis regulation in the HepG2 cell line, demonstrated that fluvastatin induced AMPK and LKB phosphorylation and activation as a result of Sirtuin 6 activation with downstream phosphorylated sterol regulatory element binding protein‐1 that prevented lipid accumulation in hepatocytes [ 64 ].…”