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Breaking down hepatic lipid production
Lipid accumulation in the liver, a condition called hepatic steatosis, often develops in metabolic syndromes, such as obesity and type 2 diabetes, and can potentially cause liver cirrhosis and failure and hepatocellular carcinoma. The de novo synthesis of lipids contributes to lipid accumulation and is inhibited by Lipin1, which suppresses the activity of the SREBP family of transcription factors, resulting in decreased expression of genes encoding lipogenic factors. In their search for new targets of the SCFβ-TRCP E3 ubiquitin ligase complex, Shimizu et al. determined that phosphorylation mediated by mTORC1 and CKI enabled Lipin1 to be degraded by SCFβ-TRCP. Compared to their wild-type counterparts, hepatocytes lacking β-TRCP1 had more Lipin1, decreased expression of SREBP target genes, and reduced triglyceride content. Moreover, mice with a deficiency of β-TRCP1 were protected against diet-induced fatty liver, suggesting that treatments that target this pathway could prevent hepatic steatosis.
