Abstract
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in Western countries, characterized by excessive fat storage in the form of lipid droplets (LDs) in hepatocytes; it is also called Metabolic-Associated Steatotic Liver Disease (MASLD), if coexisting with at least one cardiometabolic risk factor. Bergamot polyphenols (BPF) have been shown to counteract hepatic LD accumulation through potent lipogenesis suppression and associated metabolic benefits in Wistar rats, but their liver-specific anti-lipogenic effects may be species- and strain-dependent. RESULTS AND METHODS: To address this issue we examined the effect of a cafeteria diet (CAF) and BPF in C3H/HeOuJ mice, which are considered resistant to diet-induced MASLD and fibrosis. Interestingly, a 15-week CAF diet led to a robust LD accumulation, weak portal and focal inflammation, and induced a higher expression of lipogenesis (Acly)- but not fibrosis-related (Col1a) genes in C3H/HeOuJ livers. This was associated with a significant increase in blood glucose, triglycerides, and total cholesterol levels, and a decrease in caecal short-chain fatty acids (SCFAs). Importantly, mice co-treated with BPF showed strongly reduced steatosis compared to CAF mice, lower blood glucose and triglyceride levels, stimulation of hepatic autophagy, and a reduced Acly gene and protein expression, followed by a more than doubled and tripled production of total SCFAs and butyric acid, respectively. CONCLUSIONS: In conclusion, while CAF diet supplementation in C3H/HeOuJ mice proves to be a suitable model of MASLD with deficient SCFA production, BPF confirms its potency to prevent murine MASLD by pleiotropic mechanisms, including beneficial effects on SCFA content, hepatic autophagy, and lipogenesis.