Modulation of liver lipid metabolic pathways by central nervous system ER stress

Metabolic dysfunction-associated steatotic liver disease (MASLD), considered as the hepatic manifestation of metabolic syndrome, can increase the risk for cardiometabolic diseases. Accumulating reports have implicated the central nervous system in MASLD pathogenesis, specifically endoplasmic reticulum (ER) stress in subfornical organ (SFO) to hypothalamic paraventricular nucleus (PVN) projecting neurons (SFO→PVN). Here, we investigated how ER stress in this neural circuit influences hepatic lipid regulatory pathways that may contribute to MASLD development during obesity. Hepatic steatosis was elicited by feeding C57BL/6J male mice a high-fat diet for 11 wk. Intersectional viral targeting was used to inhibit ER stress in SFO→PVN neurons to examine the contribution of ER stress in this circuit to hepatic lipid acquisition and disposal genes during obesity. Inhibition of ER stress in SFO→PVN neurons of obese mice resulted in a reduction in hepatic triglycerides and lipid acquisition genes that was paralleled by a reduction in liver tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis. Moreover, hepatic tyrosine hydroxylase expression was positively correlated with lipid acquisition but not disposal pathways. These results indicate that ER stress in SFO→PVN neurons may contribute to MASLD through sympathetic nervous system influences, primarily on hepatic lipid acquisition.<b>NEW & NOTEWORTHY</b> Endoplasmic reticulum stress in SFO→PVN neurons modulates hepatic lipid acquisition and disposal pathways during obesity-induced hepatic steatosis. Hepatic tyrosine hydroxylase levels are positively correlated with liver triglyceride levels and lipid acquisition pathway-related genes in diet-induced obese animals.