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ATF4-mediated CD36 Upregulation Contributes to Palmitate-induced Lipotoxicity in Hepatocytes.
American Journal of Physiology. Gastrointestinal and Liver Physiology 2023 Februrary 29
Hepatic lipotoxicity, the deleterious effects of ectopic lipid accumulation in hepatocytes, plays a central role in the pathogenesis of non-alcoholic fatty liver disease; however, the underlying mechanisms remain elusive. Here, using palmitate exposure of hepatocytes as the in vitro hepatic lipotoxicity model, we found that palmitate exposure upregulates expression of CD36, a class B scavenger receptor mediating long-chain fatty acids uptake, in hepatocytes. Despite being a well-established target gene of PPARγ transactivation in various cell types, our data demonstrated that the palmitate-induced CD36 upregulation in hepatocytes is in fact PPARγ-independent. We previously reported that the activation of ATF4, one of three canonical pathways activated upon ER stress induction, contributes to palmitate-triggered lipotoxicity in hepatocytes. In this study, our data revealed for the first time that ATF4 plays a critical role in mediating hepatic CD36 expression. Genetic inhibition of ATF4 attenuated CD36 upregulation induced by either palmitate or ER stress inducer tunicamycin in hepatocytes. In mice, tunicamycin upregulates liver CD36 expression, whereas hepatocyte-specific ATF4 knockout mice manifest lower hepatic CD36 expression when compared to control animals. Furthermore, we demonstrated that CD36 upregulation upon palmitate exposure represents a feedforward mechanism in that siRNA knockdown of CD36 in hepatocytes blunted ATF4 activation induced by both palmitate and tunicamycin. Lastly, we confirmed that the ATF4-CD36 pathway activation contributes to palmitate-induced hepato-lipotoxicity as genetic inhibition of either ATF4 or CD36 alleviated cell death and intracellular triacylglycerol accumulation. Collectively, our data demonstrate that CD36 upregulation by ATF4 activation contributes to palmitate-induced hepatic lipotoxicity.
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