Hilpda gene expression in steatotic liver is regulated by peroxisome proliferator-activated receptor γ

Abstract Hypoxia-inducible lipid droplet–associated protein (HILPDA) promotes hepatic lipid accumulation. Hilpda gene expression is directly regulated by hypoxia-inducible factors (HIF1A and HIF1B) and the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα). However, whether the expression of Hilpda is regulated by peroxisome proliferator-activated receptor gamma (PPARγ) in fatty liver remains unclear. In this study, we investigated the role of PPARγ in regulating Hilpda expression in fatty liver. The analysis of publicly available microarray datasets revealed that Hilpda expression is significantly increased in the fatty liver of patients with metabolic dysfunction–associated steatotic liver disease, as well as in obese and type 2 diabetes model ob/ob mice, high-fat diet-fed mice, and mice fed a high-fat, cholesterol-, and fructose-enriched diet, all of which exhibit elevated PPARγ expression. In contrast, Ppara/PPARA expression in the liver remained unchanged in mouse fatty liver models and was decreased in human MASLD liver samples. Hilpda expression in the fatty liver of ob/ob mice was further induced by PPARγ ligand treatment; however, this induction was significantly repressed in liver-specific PPARγ-deficient mice. Complementary in vitro analyses showed that ectopic expression and ligand activation of PPARγ in liver-derived AML-12 cells were sufficient to induce Hilpda transcription, whereas Hif1a and Hif1b were only modestly induced, indicating minimal contribution of HIF-1 signaling. Overall, our study identifies Hilpda as a key component of the liver PPARγ-driven gene network, highlighting its role as a metabolic effector that adapts to pathological lipid accumulation.