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REDD1 deficiency protects against nonalcoholic hepatic steatosis induced by high-fat diet. Dumas Karine,Ayachi Chaima,Gilleron Jerome,Lacas-Gervais Sandra,Pastor Faustine,Favier François B,Peraldi Pascal,Vaillant Nathalie,Yvan-Charvet Laurent,Bonnafous Stéphanie,Patouraux Stéphanie,Anty Rodolphe,Tran Albert,Gual Philippe,Cormont Mireille,Tanti Jean-François,Giorgetti-Peraldi Sophie FASEB journal : official publication of the Federation of American Societies for Experimental Biology 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-1α and CPT-1 expression, involved in fatty acid oxidation. In conclusion, loss of REDD1 protects mice from the development of hepatic steatosis. 10.1096/fj.201901799RR