Involvement of multiple pathways in the protection of liver against high-fat diet-induced steatosis by betaine

The mechanism of lipotropic action provided by betaine in early diet-induced liver steatosis was investigated. Male rats received a high-fat liquid diet (HF) for 3 wk. HF intake resulted in a significant accumulation of triacyglycerol and cholesterol in the liver. Phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) was decreased, while protein expression of liver-X-receptor α (LXRα) and nuclear sterol regulatory element binding protein-1c (nSREBP-1c) was enhanced. Betaine supplement at 1% in HF inhibited hepatic triacyglycerol accumulation, but elevated serum cholesterol and triacyglycerol levels. Phosphorylation of AMPK and ACC was normalized, and induction of LXRα and nSREBP-1c was prevented. HF intake down-regulated betaine-homocysteine methyltransferase and increased homocysteine levels, both of which were blocked by betaine. Betaine supplementation elevated hepatic apolipoprotein B and serum phosphatidylcholine levels. The results suggest that both inhibition of lipid synthesis and enhancement of its secretion are involved in the anti-steatotic activity of betaine.