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).
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.
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.
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.
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.
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)
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Journal of Hepatology
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
Author names in bold designate shared co-first authorship
- Management of the metabolic syndrome and type 2 diabetes through lifestyle modification.Ann Rev Nutr. 2009; 29: 223-256
- Dietary fructose in nonalcoholic fatty liver disease.Hepatology. 2013; 57: 2525-2531
- Inflammatory links between obesity and metabolic disease.J Clin Invest. 2011; 121: 2111-2117
- Endoplasmic reticulum stress in liver disease.J Hepatol. 2011; 54: 795-809
- Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates.Proc Natl Acad Sci U S A. 2006; 103: 16454-16459
- Saturated fatty acids induce c-Src clustering within membrane subdomains leading to JNK activation.Cell. 2011; 147: 173-184
- Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease.Prog Lipid Res. 2013; 52: 165-174
- Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes.Science. 2004; 306: 457-461
- The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1α/ATF6α complex.Cell Metab. 2011; 13: 160-169
- Recent insights into stearoyl-CoA desaturase-1.Curr Opin Lipidol. 2003; 14: 255-261
- Regulation of stearoyl-CoA desaturases and role in metabolism.Prog Lipid Res. 2004; 43: 91-104
- Postnatal dietary fat influences mRNAS involved in myelination.Dev Neurosci. 1992; 14: 61-68
- Selective activation of phospholipase D2 by unsaturated fatty acid.FEBS Lett. 1999; 454: 42-46
- Regulation of stearoyl-CoA desaturase by polyunsaturated fatty acids and cholesterol.J Lipid Res. 1999; 40: 1549-1558
- Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites.Hepatology. 2010; 52: 774-788
- Fatty acids and the endoplasmic reticulum in nonalcoholic fatty liver disease.BioFactors. 2011; 37: 8-16
- Liver gene expression analysis reveals endoplasmic reticulum stress and metabolic dysfunction in SCD1-deficient mice fed a very low-fat diet.Physiol Genomics. 2008; 33: 361-372
- Hepatic stearoyl-CoA desaturase-1 deficiency protects mice from carbohydrate-induced adiposity and hepatic steatosis.Cell Metab. 2007; 6: 484-496
- Hepatic oleate regulates adipose tissue lipogenesis and fatty acid oxidation.J Lipid Res. 2015; ([Epub ahead of print])
- Stearoyl-CoA desaturase 1 gene expression is necessary for fructose-mediated induction of lipogenic gene expression by sterol regulatory element-binding protein-1c-dependent and independent mechanisms.J Biol Chem. 2004; 279: 25164-25171
- Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease.Semin Liver Dis. 2008; 28: 360-369
- Structural and functional link between the mitochondrial network and the endoplasmic reticulum.Int J Biochem Cell Biol. 2009; 41: 1817-1827
- ER stress in cardiovascular disease.J Mol Cell Cardiol. 2010; 48: 1105-1110
- Scd3–a novel gene of the stearoyl-CoA desaturase family with restricted expression in skin.Genomics. 2001; 71: 182-191
- Oleoyl-CoA is the major de novo product of stearoyl-CoA desaturase 1 gene isoform and substrate for the biosynthesis of the Harderian gland 1-alkyl-2,3-diacylglycerol.J Biol Chem. 2001; 276: 39455-39461
- Lack of stearoyl-CoA desaturase-1 function induces a palmitoyl-CoA Delta6 desaturase and represses the stearoyl-CoA desaturase-3 gene in the preputial glands of the mouse.J Lipid Res. 2002; 43: 2146-2154
- Oleate reverses palmitate-induced insulin resistance and inflammation in skeletal muscle cells.J Biol Chem. 2008; 283: 11107-11116
- Metabolic control through the PGC-1 family of transcription coactivators.Cell Metab. 2005; 1: 361-370
- Hyperlipidemic effects of dietary saturated fats mediated through PGC-1β coactivation of SREBP.Cell. 2005; 120: 261-273
- Non-CpG methylation of the PGC-1α promoter through DNMT3B controls mitochondrial density.Cell Metab. 2009; 10: 189-198
Published online: March 11, 2016
Accepted: March 1, 2016
Received in revised form: February 24, 2016
Received: May 11, 2015
© 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.