Lutein mitigates high-fat-diet induced hepatic lipid accumulation and fibrosis by targeting Hmgcs1 in marine fish

This study investigated the alleviating effects of dietary lutein (LU) against high-fat diet (HFD)-induced hepatic lipid accumulation and fibrosis in black seabream ( Acanthopagrus schlegelii ). A 10-week feeding trial demonstrated that while LU did not alter growth performance, it significantly mitigated HFD-induced visceral adiposity. LU supplementation markedly lowered serum triglycerides (TG), cholesterol (CHO), and low-density lipoprotein cholesterol (LDL-C) levels compared to the HFD group. Histological analysis confirmed reduced hepatic lipid droplet accumulation, accompanied by decreased malondialdehyde (MDA) and reactive oxygen species (ROS) levels, alongside enhanced antioxidant enzyme activities. Transcriptomic profiling revealed that LU downregulated genes involved in cholesterol biosynthesis and fibrosis, with 3-hydroxy-3-methylglutaryl-CoA synthase 1 ( hmgcs1 ) identified as a key target. Molecular docking and cellular thermal shift assay results supported an interaction between LU and Hmgcs1. In the established black seabream hepatocytes, LU suppressed oleic acid- (OA)-induced cholesterol biosynthesis and fibrotic gene expression, whereas hmgcs1 knockdown enhanced and hmgcs1 overexpression attenuated these protective effects. Collectively, dietary LU reduced HFD-induced hepatic lipid accumulation, oxidative stress, and fibrotic responses in black seabream, at least partly through downregulation of hmgcs1 -associated cholesterol biosynthesis.