APOC3 Promotes DGAT2-Dependent Triglyceride Accumulation in Hepatocytes During Early Metabolic Dysfunction.

Area of Science:

• Hepatology
• Molecular Biology
• Metabolic Disease Research

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) involves liver fat accumulation, often linked to obesity and insulin resistance.
• Apolipoprotein C-III (APOC3) is known to regulate plasma triglycerides, but its direct role within liver cells in lipid buildup is not well understood.

Purpose of the Study:

• To investigate the hepatocyte-intrinsic function of APOC3 in intracellular triglyceride synthesis during the early stages of metabolic dysfunction.
• To determine if APOC3 contributes to hepatic lipid accumulation in MASLD.

Main Methods:

• Utilized db/db mouse models to observe early hepatic lipid accumulation.
• Performed transcriptomic profiling to identify upregulated genes in lipid metabolism.
• Conducted gain- and loss-of-function studies in HepG2 cells to assess APOC3's impact on triglyceride levels.
• Investigated the mechanistic link between APOC3 and diacylglycerol acyltransferase 2 (DGAT2).

Main Results:

• APOC3 was found to be upregulated in the liver during early metabolic dysfunction in db/db mice.
• APOC3 overexpression in HepG2 cells increased intracellular triglyceride content, while knockdown reduced it.
• APOC3 selectively enhanced DGAT2 expression and activity, promoting triglyceride synthesis without affecting major lipogenic transcription factors.
• APOC3 amplified DGAT2 expression and lipid accumulation under conditions stimulating de novo lipogenesis.

Conclusions:

• APOC3 plays a direct, hepatocyte-intrinsic role in promoting hepatic triglyceride accumulation.
• The APOC3-DGAT2 axis is identified as a critical pathway contributing to lipid buildup in metabolic liver disease.
• Targeting the APOC3-DGAT2 interaction may offer a therapeutic strategy for MASLD.