title: NHE1 deficiency in liver: implications for non-alcoholic fatty liver disease.
abstract: Non-alcoholic fatty liver disease NAFLD is closely associated with the dysregulation of lipid homeostasis. Diet-induced hepatic steatosis, which can initiate NAFLD progression, has been shown to be dramatically reduced in mice lacking the electroneutral Na(+)/H(+) exchanger NHE1 (Slc9a1). In this study, we investigated if NHE1 deficiency had effects in liver that could contribute to the apparent protection against aberrant lipid accumulation. RT-PCR and immunoblot analyses of wild-type and NHE1-null livers revealed an expression profile that strongly suggested attenuation of both de novo lipogenesis and hepatic stellate cell activation, which is implicated in liver fibrosis. This included upregulation of the farnesoid X receptor FXR, peroxisome proliferator-activated receptor PPARγ, its co-activator PGC1α, and sestrin 2, an antioxidant protein involved in hepatic metabolic homeostasis. Furthermore, expression levels of the pro-lipogenic liver X receptor LXRα, and acetyl CoA carboxylases 1 and 2 were downregulated. These changes were associated with evidence of reduced cellular stress, which persisted even upon exposure to a high-fat diet, and the better preservation of insulin signaling, as evidenced by protein kinase B/Akt phosphorylation (Ser473). These results indicate that NHE1 deficiency may protect against NAFLD pathogenesis, which is significant given the availability of highly specific NHE1 inhibitors.
authors: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, United States. Electronic address: prasadvm@ucmail.uc.edu.
authors: Vikram
authors: V
authors: Prasad
authors: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, United States.
authors: Shivani
authors: S
authors: Chirra
authors: Department of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH 45267, United States.
authors: Rohit
authors: R
authors: Kohli
authors: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, United States.
authors: Gary E
authors: GE
authors: Shull
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D004041:Dietary Fats / Q000008:administration & dosage; D059865:Endoplasmic Reticulum Stress; D005234:Fatty Liver / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D018384:Oxidative Stress; D015398:Signal Transduction; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D027682:Cation Transport Proteins; D004041:Dietary Fats; D007328:Insulin; C490997:Slc9a1 protein, mouse; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers
keywords: Insulin resistance; Liver fibrosis; Metabolic syndrome; NHE1; Obesity; Steatohepatitis