A novel pathway regulating lipid biosynthesis by fatty acids

January 11, 2024 This article has been reviewed according to Science X's editorial process and policies . Editors have highlighted the following attributes while ensuring the content's credibility: fact checked peer reviewed publication trusted source proofread by University of Tsukuba Researchers have been studying the transcription factor, SREBP, a critical regulator of lipid biosynthesis.

Precursor SREBP proteins, located in the endoplasmic reticulum (ER) of the cell, are transported through the Golgi apparatus to the nucleus. Here, they promote the transcription of genes associated with lipid biosynthesis, playing a pivotal role in regulating cholesterol. The paper is published in the journal PNAS Nexus .

SREBP 1c, a specific member of the SREBP family, is known to activate fatty acid synthesis . Interestingly, this process is inhibited by polyunsaturated fatty acids . The exact mechanism behind this regulation, however, remains to be elucidated. 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.

More information: Song Iee Han et al, Rhomboid protease RHBDL4/RHBDD1 cleaves SREBP 1c at endoplasmic reticulum monitoring and regulating fatty acids, PNAS Nexus (2023). DOI: 10.1093/pnasnexus/pgad351 Journal information: PNAS Nexus Provided by University of Tsukuba.