ATF4-mediated CD36 Upregulation Contributes to Palmitate-induced 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.PMID:36852918 | DOI:10.1152/ajpgi.00163.2022
Source: American Journal of Physiology. Gastrointestinal and Liver Physiology - Category: Physiology Authors: Source Type: research