BTG1 ameliorates liver steatosis by decreasing stearoyl-CoA desaturase 1 (SCD1) abundance and altering hepatic lipid metabolism

Abstract

Liver steatosis, a condition in which lipid accumulates in liver cells, is a leading cause of many liver diseases. The livers of patients with hepatocellular carcinoma, a cancer characterized by liver steatosis, have decreased abundance of the transcription cofactor BTG1 (B cell translocation gene 1). We showed that the livers of db/db mice, which are a genetic model of obesity, had decreased BTG1 mRNA and protein abundance. BTG1 overexpression ameliorated liver steatosis in db/db mice, whereas knockdown of BTG1 induced liver steatosis in wild-type mice. Consistent with these changes, we found that BTG1 decreased triglyceride accumulation in cultured hepatocytes. BTG1 overexpression inhibited the expression of the gene encoding stearoyl-CoA desaturase 1 (SCD1), an enzyme involved in the synthesis of fatty acids, by suppressing the activity of activating transcription factor 4 (ATF4). Knockdown of SCD1 prevented liver steatosis in wild-type mice induced by knockdown of BTG1. Conversely, the ability of BTG1 overexpression to ameliorate liver steatosis in db/db mice was negated by ATF4 overexpression. Moreover, BTG1 transgenic mice were resistant to liver steatosis induced by a high-carbohydrate diet. BTG1 abundance was decreased by this diet through a pathway that involved mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase 1 (S6K1), and cAMP response element-binding protein (CREB). Together, our study identifies a role of BTG1 in regulating hepatic lipid metabolism and specifically in preventing ATF4 and SCD1 from inducing liver steatosis.