The research team elucidated a novel cleavage mechanism of SREBP-1c, a protein involved in fatty acid synthesis, and confirmed its regulation by fatty acids. The cleavage of SREBP-1c occurs in the endoplasmic reticulum, with the rhomboid protease RHBDL4, located in the ER membrane, identified as a new cleavage enzyme for SREBP-1c. This cleavage process is activated by saturated fatty acids and deactivated by polyunsaturated fatty acids, suggesting that RHBDL4’s activity is modulated by the type of fatty acid. Additionally, the team discovered a unique mechanism where the VCP complex extracts the cleaved SREBP-1c protein from the endoplasmic reticulum. In the livers of mice deficient in the RHBDL4 gene and fed a high-fat and high-cholesterol diet, the activation of SREBP-1c cleavage was suppressed. This inhibited the expression of a group of target genes involved in fatty acid synthesis, polyunsaturated fatty acid synthesis and uptake, and lipoprotein secretion, which improved fatty liver pathophysiology, as observed in wild-type mice.

The RHBDL4-SREBP-1c pathway, uncovered in this study, represents a lipid homeostasis mechanism regulated by fatty acids. This groundbreaking discovery is anticipated to pave the way for developing new therapeutic strategies for metabolic disorders and lifestyle-related diseases stemming from abnormal lipid metabolism.

This work was supported by Grants-in-Aid for Scientific Research on Innovative Areas program (Inflammation Cellular Sociology) JP17H06395 (to H.S.), Scientific Research (A) 15H02541 and 18H04051 (to H.S.), and Scientific Research (C) 16K01811 and 19K11737 (to S.-I.H.) from the Ministry of Science, Education, Culture, and Technology of Japan; AMED-CREST Grant Number 16gm0910003h0002 (to H.S.) from the Japan Agency for Medical Research and Development, AMED; and Ono Medical Research Foundation (to S.-I.H.).