Regulated in Development and DNA Damage Response 1 Protects Hepatocytes Against Palmitate-induced Lipotoxicity

Obesity induces hepatic steatosis triggering hepatic injury by lipotoxicity and can progress to nonalcoholic fatty liver disease. Regulated in development and DNA damage response 1 (REDD1) is a stimulation-inducible protein that involves in cell death, proliferation, and metabolism. In this study, we identified REDD1 induction in palmitic acid (PA)-mediated hepatocytotoxicity and its role. First, we compared the PA effects on cell viability and lipogenesis in Huh7, HepG2, and H4IIE cells, respectively. Huh7 cells were found to be the optimal cells for studying PA-induced lipotoxicity based on dose-dependent cytotoxicity and the induction of proteins related to lipogenesis. REDD1 was upregulated in PA-treated hepatocytes via a transcription-dependent mechanism. Moreover, we observed that REDD1 overexpression protected PA-derived cytotoxicity and intracellular lipid accumulation. We also examined the elevated REDD1 levels in the livers of three mice models with fatty liver: ethanol-containing diet, highcholesterol diet, or high-fat diet-fed mice. Our findings proved that REDD1 may be a candidate molecule that attenuates susceptibility to PA-induced lipotoxic liver injury