Hawthorn total flavonoids ameliorate hyperlipidemia through AMPK/SREBP1-c and PPARα/PGC-1α/CPT-1A pathway activation and gut microbiota modulation.

The increased prevalence of hyperlipidemia significantly affects human health worldwide. Although drug treatment is very effective, the harm to the human body cannot be ignored. Improvement of lipid metabolism by natural medicinal and food homologous products is an effective approach to ameliorate hyperlipidemia and it has gradually become a research focus. In this research, we adopted HepG2 cell models and high-fat-diet-fed C57BL/6j mouse models to explore the effect of hawthorn total flavonoids (HTF) on hyperlipidemia. Moreover, we utilized western blot and gut microbiota analysis to elucidate the specific mechanism of HTF's influence on hyperlipidemia. We found that HTF significantly alleviated hyperlipidemia and its complications, as manifested by reduced body weight gain and fat accumulation, and improved the disorder of intestinal microorganisms. HTF protected the liver, reducing aspartate transaminase and lactate dehydrogenase levels, and ameliorating inflammatory infiltration. Fat droplet amounts and necrotic cell numbers in liver cells were also decreased. Mechanistically, HTF promoted AMP-activated protein kinase phosphorylation, inhibited sterol regulatory element binding protein 1c expression, downregulating the expression of lipid synthesis-related proteins (acetyl CoA carboxylase, fatty acid synthase, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase), thus suppressing liver lipid synthesis. HTF also functioned as a natural peroxisome proliferator-activated receptor α (PPARα) agonist. Activated PPARα enhanced mitochondrial oxidation and lipid consumption via upregulating carnitine palmitoyltransferase 1A. Peroxisome proliferator-activated receptor-γ coactivator expression was also elevated, activating mitochondrial activity, increasing cholesterol 7α-hydroxylase activity and cholesterol consumption, and reducing blood lipids. Additionally, HTF regulated intestinal flora abundance, restored the ratio of Firmicutes to Bacteroidetes, balanced gut-liver axis crosstalk, and alleviated hyperlipidemia. The results demonstrated that HTF alleviated the pathological symptoms caused by hyperlipidemia, and had a certain protective effect on the liver. HTF also stimulated the lipid metabolism pathway and accelerated lipid consumption. © 2025 Society of Chemical Industry.