脂肪甘油三酯脂肪酶
内质网
生物
脂蛋白脂酶
内分泌学
内科学
甘油三酯
脂质代谢
脂滴
细胞生物学
生物化学
脂肪组织
胆固醇
医学
作者
Hyunbae Kim,Zhenyuan Song,Ren Zhang,Brandon S.J. Davies,Kezhong Zhang
出处
期刊:Science Signaling
[American Association for the Advancement of Science (AAAS)]
日期:2023-01-17
卷期号:16 (768)
标识
DOI:10.1126/scisignal.add6702
摘要
The endoplasmic reticulum (ER)–tethered, liver-enriched stress sensor CREBH is processed in response to increased energy demands or hepatic stress to release an amino-terminal fragment that functions as a transcription factor for hepatic genes encoding lipid and glucose metabolic factors. Here, we discovered that the carboxyl-terminal fragment of CREBH (CREBH-C) derived from membrane-bound, full-length CREBH was secreted as a hepatokine in response to fasting or hepatic stress. Phosphorylation of CREBH-C mediated by the kinase CaMKII was required for efficient secretion of CREBH-C through exocytosis. Lipoprotein lipase (LPL) mediates the lipolysis of circulating triglycerides for tissue uptake and is inhibited by a complex consisting of angiopoietin-like (ANGPTL) 3 and ANGPTL8. Secreted CREBH-C blocked the formation of ANGPTL3-ANGPTL8 complexes, leading to increased LPL activity in plasma and metabolic tissues in mice. CREBH-C administration promoted plasma triglyceride clearance and partitioning into peripheral tissues and mitigated hypertriglyceridemia and hepatic steatosis in mice fed a high-fat diet. Individuals with obesity had higher circulating amounts of CREBH-C than control individuals, and human CREBH loss-of-function variants were associated with dysregulated plasma triglycerides. These results identify a stress-induced, secreted protein fragment derived from CREBH that functions as a hepatokine to stimulate LPL activity and triglyceride homeostasis.
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