JMJD8 facilitates hepatic lipid deposition and metabolic dysfunction

Area of Science:

• Biochemistry
• Metabolic Disease
• Lipid Metabolism

Background:

• Jumonji domain-containing 8 (JMJD8) regulates lipid droplets in adipocytes.
• Perilipin-2 (PLIN2) is implicated in hepatic steatosis.
• The role of JMJD8 in liver lipid metabolism was previously undefined.

Purpose of the Study:

• To investigate the role of JMJD8 in hepatic lipid accumulation and metabolic dysfunction.
• To determine if JMJD8 regulates lipid metabolism in the liver.

Main Methods:

• Generated liver-specific Jmjd8 knockout (Jmjd8^LKO) mice.
• Administered high-fat diet (HFD) and Gubra Amylin NASH (GAN) diet to mice.
• Performed lipidomic analyses and assessed metabolic parameters (insulin sensitivity, glucose tolerance).

Main Results:

• JMJD8 expression is elevated in HFD- and GAN-induced fatty liver.
• Jmjd8^LKO mice showed reduced hepatic triglyceride accumulation under both diets.
• Lipidomics revealed decreased storage lipids and increased membrane phospholipids in Jmjd8^LKO livers.
• Jmjd8^LKO mice exhibited improved insulin sensitivity and glucose tolerance on HFD.
• JMJD8's prosteatotic effect is independent of PLIN2.

Conclusions:

• JMJD8 promotes hepatic steatosis and metabolic dysfunction, particularly under HFD.
• JMJD8 influences lipid class distribution, shifting from storage to membrane phospholipids.
• JMJD8 is a key regulator of hepatic lipid homeostasis and glucose metabolism.
• JMJD8 represents a potential therapeutic target for metabolic-associated fatty liver disease.