Editors' ChoiceMetabolism

New connections: New targets for fighting hepatic steatosis

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Science Signaling  21 Feb 2017:
Vol. 10, Issue 467, eaam9988
DOI: 10.1126/scisignal.aam9988

Insight into the signaling pathways that regulate de novo lipogenesis may lead to new treatments for hepatic steatosis.

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease characterized by the excessive hepatic accumulation of lipids and associated with metabolic syndromes, such as obesity. NAFLD includes simple fatty liver and nonalcoholic steatohepatitis (NASH), which results in liver fibrosis, cirrhosis, and dysfunction and can lead to hepatocellular carcinoma. A process that contributes to hepatic steatosis is de novo lipogenesis, which requires the induction of genes encoding lipogenic enzymes by transcription factors, such as USF1 and those in the SREBP family. In hepatocytes stimulated with insulin or fed mice, Viscarra et al. found that phosphorylation of the transcriptional coactivator MED17 was increased, which enabled USF1 to activate lipogenic enzyme–encoding genes. This phosphorylation event, which was mediated by the kinase CK2, occurred only if MED17 was not previously phosphorylated by p38, a kinase that is activated by fasting. Knockdown of CK2 or administration of a CK2 inhibitor reduced lipogenesis and triglyceride content in the liver in mice. Thus, pharmacological CK2 inhibition could be developed as a strategy to treat hepatic steatosis.

In related studies, Xiao et al. and Shimizu et al. investigated the inhibition of de novo lipogenesis or the regulation of an inhibitor of this process. Noting that the transcription cofactor BTG1 is decreased in hepatocellular carcinoma, Xiao et al. showed that BTG1 abundance was also decreased in db/db mice, which are a genetic model of obesity. BTG1 suppressed the transcription of a gene encoding stearoyl–coenzyme A (CoA) desaturase 1 (SCD1), an enzyme involved in fatty acid synthesis. Hepatic overexpression of BTG1 reduced hepatic steatosis in db/db mice and protected wild-type mice from diet-induced fatty liver. Lipin1 suppresses the activity of the SREBP family of transcription factors, and Shimizu et al. determined that after phosphorylation by the kinase complex mTORC1 and CKI, Lipin1 was degraded by the SCFβ-TRCP E3 ubiquitin ligase complex. Hepatocytes with β-TRCP1 knockdown had more Lipin1, decreased expression of SREBP target genes, and reduced triglyceride content than control hepatocytes. Moreover, like the mice that overexpressed BTG1 in the liver, mice genetically deficient in β-TRCP1 were protected against diet-induced fatty liver. Together, these results suggest that understanding the signaling pathways that regulate de novo lipogenesis may lead to new treatments for hepatic steatosis.

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