Endoplasmic Reticulum Associated Lipolysis Regulates Hepatic Fat Synthesis and Turnover [RNA-seq]

Hepatic TG and CE synthesis, lipolysis and transport are tightly regulated by nutritional status, and disruption of this homeostasis contributes to MASLD pathogenesis. We have found that an endoplasmic reticulum-localized arylacetamide deacetylase (AADAC) catalyzes hepatic TG/CE turnover and suppresses SREBP- and LXR-regulated lipogenesis and fatty acid esterification.

Consequently, AADAC deficiency in mice leads to increased hepatic lipid synthesis, exacerbated steatosis, and impaired whole-body metabolism during Western-type diet feeding. These findings implicate AADAC as an important regulator of hepatic neutral lipid metabolism, linking endoplasmic reticulum cholesteryl ester hydrolysis as a modulator of lipid synthesis, and suggest its potential role in limiting MASLD pathogenesis under conditions of chronic overnutrition.