Restoration of the ER stress response protein TDAG51 in hepatocytes mitigates NAFLD in mice.

Autor:	Yousof TR; Division of Nephrology, Department of Medicine, The Research Institute of St. Joe's Hamilton and the Hamilton Centre for Kidney Research, McMaster University, Hamilton, Ontario, Canada., Bouchard CC; Division of Nephrology, Department of Medicine, The Research Institute of St. Joe's Hamilton and the Hamilton Centre for Kidney Research, McMaster University, Hamilton, Ontario, Canada., Alb M; Division of Nephrology, Department of Medicine, The Research Institute of St. Joe's Hamilton and the Hamilton Centre for Kidney Research, McMaster University, Hamilton, Ontario, Canada., Lynn EG; Division of Nephrology, Department of Medicine, The Research Institute of St. Joe's Hamilton and the Hamilton Centre for Kidney Research, McMaster University, Hamilton, Ontario, Canada., Lhoták S; Division of Nephrology, Department of Medicine, The Research Institute of St. Joe's Hamilton and the Hamilton Centre for Kidney Research, McMaster University, Hamilton, Ontario, Canada., Jiang H; Department of Pediatrics, School of Medicine, University of Colorado Health Sciences Center, Aurora, Colorado, USA., MacDonald M; Division of Nephrology, Department of Medicine, The Research Institute of St. Joe's Hamilton and the Hamilton Centre for Kidney Research, McMaster University, Hamilton, Ontario, Canada., Li H; Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona, USA., Byun JH; Division of Nephrology, Department of Medicine, The Research Institute of St. Joe's Hamilton and the Hamilton Centre for Kidney Research, McMaster University, Hamilton, Ontario, Canada., Makda Y; Division of Nephrology, Department of Medicine, The Research Institute of St. Joe's Hamilton and the Hamilton Centre for Kidney Research, McMaster University, Hamilton, Ontario, Canada., Athanasopoulos M; Department of Biology, McMaster University, Hamilton, Ontario, Canada., Maclean KN; Department of Pediatrics, School of Medicine, University of Colorado Health Sciences Center, Aurora, Colorado, USA., Cherrington NJ; Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona, USA., Naqvi A; Department of Pathology and Molecular Medicine, St. Joseph's Healthcare Hamilton, McMaster University, Hamilton, Ontario, Canada., Igdoura SA; Department of Biology, McMaster University, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada., Krepinsky JC; Division of Nephrology, Department of Medicine, The Research Institute of St. Joe's Hamilton and the Hamilton Centre for Kidney Research, McMaster University, Hamilton, Ontario, Canada; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada., Steinberg GR; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Division of Endocrinology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Austin RC; Division of Nephrology, Department of Medicine, The Research Institute of St. Joe's Hamilton and the Hamilton Centre for Kidney Research, McMaster University, Hamilton, Ontario, Canada; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada. Electronic address: austinr@taari.ca.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2024 Feb; Vol. 300 (2), pp. 105655. Date of Electronic Publication: 2024 Jan 16.
DOI:	10.1016/j.jbc.2024.105655
Abstrakt:	Endoplasmic reticulum stress is associated with insulin resistance and the development of nonalcoholic fatty liver disease. Deficiency of the endoplasmic reticulum stress response T-cell death-associated gene 51 (TDAG51) (TDAG51 -/- ) in mice promotes the development of high-fat diet (HFD)-induced obesity, fatty liver, and hepatic insulin resistance. However, whether this effect is due specifically to hepatic TDAG51 deficiency is unknown. Here, we report that hepatic TDAG51 protein levels are consistently reduced in multiple mouse models of liver steatosis and injury as well as in liver biopsies from patients with liver disease compared to normal controls. Delivery of a liver-specific adeno-associated virus (AAV) increased hepatic expression of a TDAG51-GFP fusion protein in WT, TDAG51 -/- , and leptin-deficient (ob/ob) mice. Restoration of hepatic TDAG51 protein was sufficient to increase insulin sensitivity while reducing body weight and fatty liver in HFD fed TDAG51 -/- mice and in ob/ob mice. TDAG51 -/- mice expressing ectopic TDAG51 display improved Akt (Ser473) phosphorylation, post-insulin stimulation. HFD-fed TDAG51 -/- mice treated with AAV-TDAG51-GFP displayed reduced lipogenic gene expression, increased beta-oxidation and lowered hepatic and serum triglycerides, findings consistent with reduced liver weight. Further, AAV-TDAG51-GFP-treated TDAG51 -/- mice exhibited reduced hepatic precursor and cleaved sterol regulatory-element binding proteins (SREBP-1 and SREBP-2). In vitro studies confirmed the lipid-lowering effect of TDAG51 overexpression in oleic acid-treated Huh7 cells. These studies suggest that maintaining hepatic TDAG51 protein levels represents a viable therapeutic approach for the treatment of obesity and insulin resistance associated with nonalcoholic fatty liver disease. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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