Hepatic DsbA‐L protects mice from diet‐induced hepatosteatosis and insulin resistance

Hepatic insulin resistance and hepatosteatosis in diet‐induced obesity are associated with various metabolic diseases, yet the underlying mechanisms remain to be fully elucidated. Here we show that the expression levels of the disulfide‐bond A oxidoreductase‐like protein (DsbA‐L) are significantly reduced in the liver of obese mice and humans. Liver‐specific knockout or adenovirus‐mediated overexpression of DsbA‐L exacerbates or alleviates, respectively, high‐fat diet–induced mitochondrial dysfunction, hepatosteatosis, and insulin resistance in mice. Mechanistically, we found that DsbA‐L is localized in mitochondria and that its deficiency is associated with impairment of maximum respiratory capacity, elevated cellular oxidative stress, and increased JNK activity. Our results identify DsbA‐L as a critical regulator of mitochondrial function, and its down‐regulation in the liver may contribute to obesity‐induced hepatosteatosis and whole body insulin resistance.—Chen, H., Bai, J., Dong, F., Fang, H., Zhang, Y., Meng, W., Liu, B., Luo, Y., Liu, M., Bai, Y., Abdul‐Ghani, M. A., Li, R., Wu, J., Zeng, R., Zhou, Z., Dong, L. Q., Liu, F. Hepatic DsbA‐L protects mice from diet‐induced hepatosteatosis and insulin resistance. FASEB J. 31, 2314–2326 (2017). www.fasebj.org

[1]  R. Angeletti,et al.  Impact of high-fat diet on the proteome of mouse liver. , 2016, The Journal of nutritional biochemistry.

[2]  Lily Q. Dong,et al.  Endoplasmic Reticulum (ER) Localization Is Critical for DsbA-L Protein to Suppress ER Stress and Adiponectin Down-regulation in Adipocytes* , 2015, The Journal of Biological Chemistry.

[3]  N. Turner,et al.  Mitochondrial dysfunction and insulin resistance: an update , 2014, Endocrine connections.

[4]  F. Colina,et al.  High-fat diet decreases activity of the oxidative phosphorylation complexes and causes nonalcoholic steatohepatitis in mice , 2014, Disease Models & Mechanisms.

[5]  G. Shulman.  Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. , 2014, The New England journal of medicine.

[6]  Feng Dong,et al.  APPL1 Potentiates Insulin Sensitivity by Facilitating the Binding of IRS1/2 to the Insulin Receptor , 2014, Cell reports.

[7]  F. Nassir,et al.  Role of Mitochondria in Nonalcoholic Fatty Liver Disease , 2014, International journal of molecular sciences.

[8]  C. Vernochet,et al.  Mitochondria, obesity and aging , 2012, Aging.

[9]  F. Liu,et al.  Fat-Specific DsbA-L Overexpression Promotes Adiponectin Multimerization and Protects Mice From Diet-Induced Obesity and Insulin Resistance , 2012, Diabetes.

[10]  Michael Karin,et al.  A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches. , 2012, Gastroenterology.

[11]  D. S̆timac,et al.  Nonalcoholic Fatty Liver Disease/Steatohepatitis: Epidemiology, Pathogenesis, Clinical Presentation and Treatment , 2012, Digestive Diseases.

[12]  G. Dorn,et al.  BNip3 Regulates Mitochondrial Function and Lipid Metabolism in the Liver , 2012, Molecular and Cellular Biology.

[13]  Kelsey H. Fisher-Wellman,et al.  Linking mitochondrial bioenergetics to insulin resistance via redox biology , 2012, Trends in Endocrinology & Metabolism.

[14]  H. Raza.  Dual localization of glutathione S‐transferase in the cytosol and mitochondria: implications in oxidative stress, toxicity and disease , 2011, The FEBS journal.

[15]  F. Liu,et al.  Mitochondrial stress: a bridge between mitochondrial dysfunction and metabolic diseases? , 2011, Cellular signalling.

[16]  X. Leverve,et al.  Effects of a high-fat diet on energy metabolism and ROS production in rat liver. , 2011, Journal of hepatology.

[17]  A. Colao,et al.  Hepatic steatosis, low-grade chronic inflammation and hormone/growth factor/adipokine imbalance. , 2010, World journal of gastroenterology.

[18]  F. Liu,et al.  DsbA-L Alleviates Endoplasmic Reticulum Stress–Induced Adiponectin Downregulation , 2010, Diabetes.

[19]  M. Zeviani,et al.  Isolation of mitochondria for biogenetical studies: An update. , 2010, Mitochondrion.

[20]  Shuichi Kaneko,et al.  Palmitate Induces Insulin Resistance in H4IIEC3 Hepatocytes through Reactive Oxygen Species Produced by Mitochondria , 2009, Journal of Biological Chemistry.

[21]  R. DeFronzo,et al.  Mitochondrial reactive oxygen species generation in obese non-diabetic and type 2 diabetic participants , 2009, Diabetologia.

[22]  Feng Liu,et al.  A disulfide-bond A oxidoreductase-like protein (DsbA-L) regulates adiponectin multimerization , 2008, Proceedings of the National Academy of Sciences.

[23]  M. Honda,et al.  Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity. , 2008, Metabolism: clinical and experimental.

[24]  E. Araki,et al.  Impact of mitochondrial ROS production in the pathogenesis of insulin resistance. , 2007, Diabetes research and clinical practice.

[25]  Feng Liu,et al.  APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function , 2006, Nature Cell Biology.

[26]  D. Befroy,et al.  Mechanism of Hepatic Insulin Resistance in Non-alcoholic Fatty Liver Disease* , 2004, Journal of Biological Chemistry.

[27]  T. Orton,et al.  Tissue-specific Expression and Subcellular Distribution of Murine Glutathione S-transferase Class Kappa , 2004, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[28]  Gary L Gilliland,et al.  Parallel evolutionary pathways for glutathione transferases: structure and mechanism of the mitochondrial class kappa enzyme rGSTK1-1. , 2004, Biochemistry.

[29]  Xianlin Han,et al.  Decreased Hepatic Triglyceride Accumulation and Altered Fatty Acid Uptake in Mice with Deletion of the Liver Fatty Acid-binding Protein Gene* , 2003, Journal of Biological Chemistry.

[30]  J. Arenas,et al.  Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis , 2003, Hepatology.

[31]  S. Chirala,et al.  The subcellular localization of acetyl-CoA carboxylase 2. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[32]  É. Hajduch,et al.  Regulation of Glucose Transport and Glycogen Synthesis in L6 Muscle Cells during Oxidative Stress , 1999, The Journal of Biological Chemistry.

[33]  N. Holbrook,et al.  The cellular response to oxidative stress: influences of mitogen-activated protein kinase signalling pathways on cell survival. , 1998, The Biochemical journal.

[34]  D. Accili,et al.  Evidence That IRS-2 Phosphorylation Is Required for Insulin Action in Hepatocytes* , 1998, The Journal of Biological Chemistry.

[35]  A. Clerk,et al.  Stimulation of “Stress-regulated” Mitogen-activated Protein Kinases (Stress-activated Protein Kinases/c-Jun N-terminal Kinases and p38-Mitogen-activated Protein Kinases) in Perfused Rat Hearts by Oxidative and Other Stresses* , 1998, The Journal of Biological Chemistry.

[36]  J. Taylor,et al.  Glutathione S-transferase class Kappa: characterization by the cloning of rat mitochondrial GST and identification of a human homologue. , 1996, The Biochemical journal.

[37]  B. Ketterer,et al.  A novel glutathione transferase (13-13) isolated from the matrix of rat liver mitochondria having structural similarity to class theta enzymes. , 1991, The Biochemical journal.