JMJD8 facilitates hepatic lipid deposition and metabolic dysfunction.

We previously identified Jumonji domain-containing 8 (JMJD8) as a regulator of lipid droplet (LD) hypertrophy in adipocytes through modulation of AMPK-dependent perilipin-2 (PLIN2) phosphorylation. Given PLIN2's established role in hepatic steatosis, we investigated whether JMJD8 also regulates lipid accumulation in the liver. Here, we report that JMJD8 expression is significantly elevated in the livers of mice fed either a high-fat diet (HFD) or the metabolic-associated fatty liver disease (MAFLD)-inducing Gubra Amylin NASH (GAN) diet. To define the metabolic role of JMJD8 in the liver, we generated liver-specific Jmjd8 knockout (Jmjd8LKO) mice. Hepatic deletion of Jmjd8 reduced triglyceride (TG) accumulation under both dietary conditions, without affecting overall body weight or adiposity. Lipidomic analyses revealed a redistribution of lipid classes in Jmjd8 knockout livers on HFD, with decreased storage lipids and increased membrane phospholipids. Jmjd8LKO mice also displayed improved insulin sensitivity and glucose tolerance under HFD but not the GAN diet. Mechanistically, although JMJD8 interacts with PLIN2, its prosteatotic effect appears to be independent of PLIN2. These findings indicate that JMJD8 promotes hepatic steatosis and metabolic dysregulation under HFD by altering lipid class distribution, highlighting its potential as a therapeutic target in obesity-associated metabolic disease.NEW & NOTEWORTHY This study identifies Jumonji domain-containing 8 (JMJD8) as a previously unrecognized driver of hepatic steatosis and metabolic dysfunction in diet-induced fatty liver disease. Liver-specific deletion of Jmjd8 protects against triglyceride accumulation and insulin resistance, redirecting hepatic lipid composition from energy storage toward membrane remodeling. These findings establish JMJD8 as a key intracellular regulator of lipid homeostasis and glucose metabolism and highlight its potential as a therapeutic target for metabolic-associated fatty liver disease.