You are currently viewing the abstract.
View Full TextLog in to view the full text
AAAS login provides access to Science for AAAS members, and access to other journals in the Science family to users who have purchased individual subscriptions.
Register for free to read this article
As a service to the community, this article is available for free. Existing users log in.
More options
Download and print this article for your personal scholarly, research, and educational use.
Buy a single issue of Science for just $15 USD.
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.
Abstract
The SCFβ-TRCP E3 ubiquitin ligase complex plays pivotal roles in normal cellular physiology and in pathophysiological conditions. Identification of β-transducin repeat–containing protein (β-TRCP) substrates is therefore critical to understand SCFβ-TRCP biology and function. We used a β-TRCP–phosphodegron motif–specific antibody in a β-TRCP substrate screen coupled with tandem mass spectrometry and identified multiple β-TRCP substrates. One of these substrates was Lipin1, an enzyme and suppressor of the family of sterol regulatory element–binding protein (SREBP) transcription factors, which activate genes encoding lipogenic factors. We showed that SCFβ-TRCP specifically interacted with and promoted the polyubiquitination of Lipin1 in a manner that required phosphorylation of Lipin1 by mechanistic target of rapamycin 1 (mTORC1) and casein kinase I (CKI). β-TRCP depletion in HepG2 hepatocellular carcinoma cells resulted in increased Lipin1 protein abundance, suppression of SREBP-dependent gene expression, and attenuation of triglyceride synthesis. Moreover, β-TRCP1 knockout mice showed increased Lipin1 protein abundance and were protected from hepatic steatosis induced by a high-fat diet. Together, these data reveal a critical physiological function of β-TRCP in regulating hepatic lipid metabolic homeostasis in part through modulating Lipin1 stability.
