Xueqing Liu1, Maggie S Burhans2, Matthew T Flowers1, James M Ntambi3. 1. Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA. 2. Department of Nutritional Sciences, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA. 3. Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA; Department of Nutritional Sciences, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA. Electronic address: ntambi@biochem.wisc.edu.
Abstract
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.
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 humanSCD5, which synthesizes 18:1n-9, or mouseScd3, 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.
Authors: Ryan G Holzer; Eek-Joong Park; Ning Li; Helen Tran; Monica Chen; Crystal Choi; Giovanni Solinas; Michael Karin Journal: Cell Date: 2011-09-30 Impact factor: 41.582
Authors: Matthew T Flowers; Mark P Keller; YounJeong Choi; Hong Lan; Christina Kendziorski; James M Ntambi; Alan D Attie Journal: Physiol Genomics Date: 2008-04-01 Impact factor: 3.107
Authors: Romain Barrès; Megan E Osler; Jie Yan; Anna Rune; Tomas Fritz; Kenneth Caidahl; Anna Krook; Juleen R Zierath Journal: Cell Metab Date: 2009-09 Impact factor: 27.287
Authors: Ahmed Aljohani; Mohammad Imran Khan; Abram Bonneville; Changan Guo; Justin Jeffery; Lucas O'Neill; Deeba Nadeem Syed; Sarah A Lewis; Maggie Burhans; Hasan Mukhtar; James M Ntambi Journal: J Biol Chem Date: 2019-11-05 Impact factor: 5.157
Authors: Theresia Sarabhai; Sabine Kahl; Julia Szendroedi; Daniel F Markgraf; Oana-Patricia Zaharia; Cristina Barosa; Christian Herder; Frithjof Wickrath; Pavel Bobrov; Jong-Hee Hwang; John Griffith Jones; Michael Roden Journal: JCI Insight Date: 2020-05-21
Authors: Mohamed A Lounis; Karl-F Bergeron; Maggie S Burhans; James M Ntambi; Catherine Mounier Journal: Am J Physiol Endocrinol Metab Date: 2017-08-29 Impact factor: 4.310