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

Document Type

Journal Article

Publication Date

4-22-2025

Journal

American journal of physiology. Endocrinology and metabolism

DOI

10.1152/ajpendo.00392.2024

Keywords

Metabolic dysfunction-associated steatotic liver disease; central nervous system; hypothalamus; neural control; subfornical organ

Abstract

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 (CNS) in MASLD pathogenesis, specifically endoplasmic reticulum (ER) stress in subfornical organ to hypothalamic paraventricular nucleus 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 weeks. Intersectional viral targeting was used to inhibit ER stress in SFO→PVN neurons in order 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.

Department

Pharmacology and Physiology

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