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

Sci Signal. 2023 Jan 17;16(768):eadd6702. doi: 10.1126/scisignal.add6702. Epub 2023 Jan 17.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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


  • Angiopoietin-Like Protein 3
  • Angiopoietin-Like Protein 8
  • ANGPTL3 protein, human
  • ANGPTL8 protein, human
  • ANGPTL8 protein, mouse
  • Lipoprotein Lipase
  • Peptide Hormones
  • Triglycerides
  • CREB3L3 protein, human
  • Cyclic AMP Response Element-Binding Protein