Research ArticlePhysiology

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

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Science Signaling  17 May 2016:
Vol. 9, Issue 428, pp. ra50
DOI: 10.1126/scisignal.aad8581

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Altering gene expression to prevent fatty liver

Fat accumulation in the liver, a condition called hepatic steatosis, can lead to liver dysfunction and hepatocellular carcinoma. The transcription cofactor BTG1 is decreased in hepatocellular carcinoma. Here, Xiao et al. show that the amount of BTG1 was also decreased in mice that are a genetic model of obesity. BTG1 suppressed the transcription of a gene encoding an enzyme involved in fatty acid synthesis, and overexpression of BTG1 in the livers of obese mice resulted in less hepatic steatosis. In addition, mice that overexpressed BTG1 in the liver were protected against diet-induced fatty liver, suggesting that treatments that increase the activity of BTG1 could be developed to prevent hepatic steatosis.


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.

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