Scd1 deficiency causes endoplasmic reticulum stress and metabolic dysfunction in mice fed a very low‐fat diet

Abstract

We performed microarray analysis of hepatic gene expression in mice deficient in stearoyl‐CoA desaturase‐1 (Scd1) and maintained on a chow or a very low‐fat (VLF) diet for 10 days. We identified an extraordinary number of differentially expressed genes (>4000 probe sets) in the VLF Scd1−/− relative to both VLF Scd1+/+ and chow Scd1−/− mice. Transcript levels were reduced for genes involved in several facets of fatty acid metabolism including biosynthesis, elongation, desaturation, oxidation, transport, and ketogenesis. This pattern is attributable to the decreased mRNA abundance of several key lipid metabolism transcription factors, including LXRα, RXRα, PPARα, PGC‐1β, SREBP1c, and ChREBP. A robust induction of endoplasmic reticulum (ER) stress is indicated by the increased expression of stress‐induced transcription factors, including CHOP and ATF3, and several of their target mRNAs. Activation of the unfolded protein response pathway is further evidenced by increased splicing of XBP1 mRNA. The gene expression profile is also consistent with induction of an acute inflammatory response and macrophage recruitment. These results highlight the importance of monounsaturated fatty acid synthesis for maintaining metabolic homeostasis in the absence of sufficient dietary unsaturated fat and point to a novel cellular nutrient‐sensing mechanism linking fatty acid availability and/or composition to the ER stress response. Supported by NIH grants HL56593, DK58037, and DK066369.