Details

Autor(en) / Beteiligte

• Yousof, Tamana R.
• Bouchard, Celeste C.
• Alb, Mihnea
• Lynn, Edward G.
• Lhoták, Sárka
• Jiang, Hua
• MacDonald, Melissa
• Li, Hui
• Byun, Jae H.
• Makda, Yumna
• Athanasopoulos, Maria
• Maclean, Kenneth N.
• Cherrington, Nathan J.
• Naqvi, Asghar
• Igdoura, Suleiman A.
• Krepinsky, Joan C.
• Steinberg, Gregory R.
• Austin, Richard C.

Titel

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

Ist Teil von

• The Journal of biological chemistry, 2024-02, Vol.300 (2), p.105655-105655, Article 105655

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2024

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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.