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

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. A hepatokine elevates lipolysis: Increased amounts of circulating triglycerides are a risk factor for the development of cardiovascular and fatty liver diseases. Kim et al. identified a factor secreted from the liver that they called CREBH-C and that stimulated the lipolysis and clearance of circulating triglycerides. CREBH-C was generated and released from the liver in response to increased energy demands (such as those induced by fasting) or hepatic stress (such as that induced by obesity or an atherogenic high-fat diet) in mice and humans. Treating mice fed a high-fat diet with CREBH-C resulted in reduced circulating triglyceride amounts and increased triglyceride uptake by nonhepatic tissues. Thus, CREBH-C is a hepatokine that could be developed as a treatment for hypertriglyceridemia.—WW [ABSTRACT FROM AUTHOR]

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