The SCF ^β-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis

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. Here, 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.

The ins and outs of endoplasmic reticulum‐controlled lipid biosynthesis

“…There is also a strong correlation between hepatic ER pathology and the development of systemic metabolic defects such as hyperglycemia and insulin resistance, because of the central role of the liver in controlling circulating lipids. For example, the Pemt knockdown described above rescues systemic abnormalities in parallel with restoring normal hepatic ER membrane composition [120], clinical data correlate specific acyl chain TAG profiles with type 2 diabetes [127], and genetically reducing lipin degradation in mice (thereby allowing SREBP suppression) reduces high-fatdiet liver pathology and circulating insulin levels [111]. Thus, abnormal ER lipid synthesis contributes to the pathology of obesity, which explains the clinical benefit of drugs that regulate lipid enzymes such as statins (HMGCR inhibitors) as well as inhibitors of TAG production [128][129][130][131].…”

“…The in vivo relevance of this inhibitory interaction between lipin and SREBP is shown by genetic knockout of an ubiquitin ligase that targets phosphorylated lipin for degradation. Its loss elevates lipin levels in parallel with reducing SREBP target gene expression and lipid synthesis in liver cells . Interestingly, lipin phosphorylation driven by pro‐growth signaling is reversed by the CTDNEP1 phosphatase that resides at the nuclear periphery, and pro‐growth signals in yeast also control the lipin phosphorylation state via this phosphatase (Fig B) .…”

How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage

“…Lipin 1 is also modified by sumoylation, which promotes entry into the nucleus [163]. Lipin 1 protein degradation occurs through ubiquitination and proteasomal degradation [115,164,165]. At present, little is known about the transcriptional and post-translational regulation of lipin 2 and lipin 3.…”

F‐box/WD Repeat‐Containing Protein 5 Mediates the Ubiquitination of Apoptosis Signal‐Regulating Kinase 1 and Exacerbates Nonalcoholic Steatohepatitis in Mice

“…(16)(17)(18)(19)(20) For instance, the SCF FBXW7 complex plays key roles in regulating liver lipogenesis. (21,22) The SCF β-TRCP (also known as FBXW1) ligase ubiquitinates and degrades Lipin1 for regulating hepatic lipid metabolic homeostasis, (23) and additionally modulates ASK1 polyubiquitination and activation of downstream signaling during oxidative stress. (24) These evidences reveal that SCF FBXW(s) complex is closely related to metabolic pathophysiologies and has the potential ability of regulating ASK1 activity, indicating that SCF FBXW(s) ligases may be involved in ASK1 ubiquitination-dependent activation and contribute to NAFLD/NASH development.…”