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Liver gene expression analysis reveals endoplasmic reticulum stress and metabolic dysfunction in SCD1-deficient mice fed a very low-fat diet.

Abstract：

:We previously reported that mice deficient in stearoyl-CoA desaturase-1 (Scd1) and maintained on a very low-fat (VLF) diet for 10 days developed severe loss of body weight, hypoglycemia, hypercholesterolemia, and many cholestasis-like phenotypes. To better understand the metabolic changes associated with these phenotypes, we performed microarray analysis of hepatic gene expression in chow- and VLF-fed female Scd1+/+ and Scd1-/- mice. We identified an extraordinary number of differentially expressed genes (>4,000 probe sets) in the VLF Scd1-/- relative to both VLF Scd1+/+ and chow Scd1-/- mice. Transcript levels were reduced for genes involved in detoxification and 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 genes encoding key transcription factors, including LXRalpha, RXRalpha, FXR, PPARalpha, PGC-1beta, SREBP1c, ChREBP, CAR, DBP, TEF, and HLF. A robust induction of endoplasmic reticulum (ER) stress is indicated by enhanced splicing of XBP1, increased expression of the stress-induced transcription factors CHOP and ATF3, and elevated expression of several genes involved in the integrated stress and unfolded protein response pathways. 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.

journal_name

Physiol Genomics

journal_title

Physiological genomics

authors

Flowers MT,Keller MP,Choi Y,Lan H,Kendziorski C,Ntambi JM,Attie AD

doi

10.1152/physiolgenomics.00139.2007

subject

Has Abstract

pub_date

2008-05-13 00:00:00

pages

361-72

issue

eissn

1094-8341

issn

1531-2267

pii

00139.2007

journal_volume

pub_type

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Liver gene expression analysis reveals endoplasmic reticulum stress and metabolic dysfunction in SCD1-deficient mice fed a very low-fat diet.