FACI Is a Novel CREB-H-Induced Protein That Inhibits Intestinal Lipid Absorption and Reverses Diet-Induced Obesity

BACKGROUND & AIMS: CREB-H is a key liver-enriched transcription factor governing lipid metabolism. Additional targets of CREB-Hremain tobeidentifiedandcharacterized. Here, weidentified a novel fasting- and CREB-H-induced (FACI) protein that inhibits intestinal lipid absorption andalleviates diet-induced obesity inmice. METHODS: FACI was identified by reanalysis of existing transcriptomic data. Faci(-/-) mice were generated by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPRassociated 9 (Cas9)-mediated genome engineering. RNA sequencing was performed to identify differentially expressed genes in Faci(-/-) mice. Lipid accumulation in the villi was assessed by triglyceride measurement and Oil red O staining. In vitro fatty acid uptake assay was performed to verify in vivo findings. RESULTS: FACIexpressionwasenrichedinliverandintestine. FACI isaphospholipid-bindingprotein that localizes toplasma membrane and recycling endosomes. Hepatic transcription of Faci was regulated bynot onlyCREB-H, but also nutrient-responsive transcription factors sterol regulatory element-binding protein 1 (SREBP1), hepatocyte nuclear factor 4a (HNF4 alpha), peroxisome proliferator-activated receptor g coactivator-1 alpha (PGC1 alpha), and CREB, as well as fasting-related cyclic adenosine monophosphate (cAMP) signaling. Genetic knockout of Faci in mice showed an increase in intestinal fat absorption. Inaccordancewith this, Faci deficiency aggravated highfat diet-induced obesity, hyperlipidemia, steatosis, and other obesity-related metabolic dysfunction in mice. CONCLUSIONS: FACI is a novel CREB-H-induced protein. Genetic disruption of Faci in mice showed its inhibitory effect on fat absorption and obesity. Our findings shed light on a new target of CREB-H implicated in lipid homeostasis. (Cell Mol Gastroenterol Hepatol

Automated summary

A novel protein called FACI, induced by fasting and CREB-H, was found to inhibit intestinal lipid absorption and alleviate diet-induced obesity in mice. Furthermore, deficiency of FACI worsened obesity and metabolic dysfunction induced by a high-fat diet.