Journal
FASEB JOURNAL
Volume 34, Issue 4, Pages 5046-5060Publisher
WILEY
DOI: 10.1096/fj.201901799RR
Keywords
autophagy; hepatic steatosis; obesity; REDD1
Categories
Funding
- INSERM (France)
- French Government (National Research Agency, ANR) [ANR-15-CE14-0016-01, ANR-18-CE14-0019-02]
- Investments for the Future LABEX SIGNALIFE [ANR-11-LABX-0028-01]
- UCAJEDI Investments in the Future project [ANR-15-IDEX-01]
- Societe Francophone du Diabete SFD/ Abbott
- Universite Cote d'Azur
- Region Provence-Alpes-Cote-d'Azur
- Conseil General des Alpes Maritimes
- Region Sud-ProvenceAlpes-Cote-d'Azur
- GIS-IBiSA and Canceropole Provence-Alpes-Cote d'Azur
- Agence Nationale de la Recherche (ANR) [ANR-18-CE14-0019, ANR-15-CE14-0016] Funding Source: Agence Nationale de la Recherche (ANR)
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Nonalcoholic fatty liver disease is a chronic liver disease which is associated with obesity and insulin resistance. We investigated the implication of REDD1 (Regulated in development and DNA damage response-1), a stress-induced protein in the development of hepatic steatosis. REDD1 expression was increased in the liver of obese mice and morbidly obese patients, and its expression correlated with hepatic steatosis and insulin resistance in obese patients. REDD1 deficiency protected mice from the development of hepatic steatosis induced by high-fat diet (HFD) without affecting body weight gain and glucose intolerance. This protection was associated with a decrease in the expression of lipogenic genes, SREBP1c, FASN, and SCD-1 in liver of HFD-fed REDD1-KO mice. Healthy mitochondria are crucial for the adequate control of lipid metabolism and failure to remove damaged mitochondria is correlated with liver steatosis. Expression of markers of autophagy and mitophagy, Beclin, LC3-II, Parkin, BNIP3L, was enhanced in liver of HFD-fed REDD1-KO mice. The number of mitochondria showing colocalization between LAMP2 and AIF was increased in liver of HFD-fed REDD1-KO mice. Moreover, mitochondria in liver of REDD1-KO mice were smaller than in WT. These results are correlated with an increase in PGC-1 alpha and CPT-1 expression, involved in fatty acid oxidation. In conclusion, loss of REDD1 protects mice from the development of hepatic steatosis.
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