Background & Aims
High-carbohydrate diets contribute to the development of liver stress and fatty liver
disease. While saturated fatty acids are known to induce liver stress, the role of
monounsaturated fatty acids (MUFA), synthesized by the stearoyl-CoA desaturase (SCD)
family of enzymes, in regulation of liver function during lipogenic dietary conditions
remains largely unknown. The major products of SCD-catalyzed reactions are oleate
(18:1n-9) and palmitoleate (16:1n-7).
Methods
We generated mouse models with restricted exogenous MUFA supply and reduced endogenous
MUFA synthesis, in which SCD1 global knockout (GKO) or liver-specific knockout (LKO)
mice were fed a lipogenic high-sucrose very low-fat (HSVLF) or high-carbohydrate (HC)
diet. In a gain-of-function context, we introduced liver-specific expression of either
human SCD5, which synthesizes 18:1n-9, or mouse Scd3, which synthesizes 16:1n-7, into SCD1 GKO mice and fed the HSVLF diet.
Results
Lipogenic high-carbohydrate diets induced hepatic endoplasmic reticulum (ER) stress
and inflammation in SCD1 GKO and LKO mice. Dietary supplementation with 18:1n-9, but
not 18:0, prevented the HSVLF diet-induced hepatic ER stress and inflammation in SCD1
LKO mice, while hepatic SCD5, but not Scd3, expression reduced the ER stress and inflammation in GKO mice. Additional experiments
revealed liver-specific deletion of the transcriptional coactivator PGC-1α reduced
hepatic inflammatory and ER stress response gene expression in SCD1 LKO mice.
Conclusions
Our results demonstrate an indispensable role of hepatic oleate in protection against
lipogenic diet-induced hepatic injury, and PGC-1α potentiates the ER stress response
under conditions of restricted dietary oleate coupled to reduced capacity of endogenous
hepatic oleate synthesis.
Lay summary
Susceptibility to metabolic dysfunction is influenced by genetic and environmental
factors. In this study we show that modulation of two genes regulates the liver response,
including ER stress and inflammation, to a high-carbohydrate low-fat diet. We reveal
that hepatic availability of oleate, a monounsaturated fatty acid, is important for
maintenance of liver health.
Graphical abstract
Graphical Abstract
Abbreviations:
ER (endoplasmic reticulum), TG (triglycerides), CE (cholesterol esters), PL (phospholipids), FFA (free fatty acids), SFA (saturated fatty acids), MUFA (monounsaturated fatty acids), SCD (stearoyl-CoA desaturase), GKO (global knockout), HSVLF (high-sucrose very low-fat), LKO (liver-specific knockout), GLS5 (GKO liver-specific SCD5), GLS3 (GKO liver-specific Scd3), HC (high sucrose, high-carbohydrate), WT (wild-type), TLC (thin layer chromatography), GLC (gas liquid chromatography), ALT (alanine aminotransferase), UPR (unfolded protein response), DLKO (double liver knockout), ROS (reactive oxygen species)Keywords
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Article info
Publication history
Published online: March 11, 2016
Accepted:
March 1,
2016
Received in revised form:
February 24,
2016
Received:
May 11,
2015
Identification
Copyright
© 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
