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A hepatokine derived from the ER protein CREBH promotes triglyceride metabolism by stimulating lipoprotein lipase activity
Journal article   Open access   Peer reviewed

A hepatokine derived from the ER protein CREBH promotes triglyceride metabolism by stimulating lipoprotein lipase activity

Hyunbae Kim, Zhenfeng Song, Ren Zhang, Brandon S J Davies and Kezhong Zhang
Science signaling, Vol.16(768), pp.eadd6702-eadd6702
01/17/2023
DOI: 10.1126/scisignal.add6702
PMCID: PMC10080946
PMID: 36649378
url
https://pmc.ncbi.nlm.nih.gov/articles/PMC10080946/pdf/nihms-1883599.pdfView
Open Access

Abstract

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 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.
 Angiopoietin-Like Protein 3 Angiopoietin-Like Protein 8 Animals Cyclic AMP Response Element-Binding Protein - metabolism Endoplasmic Reticulum - genetics Endoplasmic Reticulum - metabolism Humans Lipid Metabolism - genetics Lipoprotein Lipase - metabolism Liver - metabolism Mice Peptide Hormones - metabolism Triglycerides

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