RT Journal Article SR Electronic T1 The SCFβ-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis JF Science Signaling JO Sci. Signal. FD American Association for the Advancement of Science SP eaah4117 DO 10.1126/scisignal.aah4117 VO 10 IS 460 A1 Shimizu, Kouhei A1 Fukushima, Hidefumi A1 Ogura, Kohei A1 Lien, Evan C. A1 Nihira, Naoe Taira A1 Zhang, Jinfang A1 North, Brian J. A1 Guo, Ailan A1 Nagashima, Katsuyuki A1 Nakagawa, Tadashi A1 Hoshikawa, Seira A1 Watahiki, Asami A1 Okabe, Koji A1 Yamada, Aya A1 Toker, Alex A1 Asara, John M. A1 Fukumoto, Satoshi A1 Nakayama, Keiichi I. A1 Nakayama, Keiko A1 Inuzuka, Hiroyuki A1 Wei, Wenyi YR 2017 UL http://stke.sciencemag.org/content/10/460/eaah4117.abstract AB 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.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.