The PNPLA3-I148M variant increases polyunsaturated triglycerides in human adipose tissue

Area of Science:

• Genetics
• Metabolic Diseases
• Lipid Metabolism

Background:

• The I148M variant in PNPLA3 is a major genetic risk factor for non-alcoholic fatty liver disease (NAFLD).
• Previous research indicated PNPLA3 is liver-specific, with PNPLA3-I148M carriers showing increased polyunsaturated triglycerides (PUFA-TGs) in the liver.
• The function of PNPLA3 in adipose tissue (AT) and its role in NAFLD pathogenesis remained unknown.

Purpose of the Study:

• To investigate whether the PNPLA3-I148M variant modifies adipose tissue metabolism in human NAFLD.
• To determine the abundance and localization of PNPLA3 protein in human adipose tissue compared to the liver.

Main Methods:

• Lipidomic profiling of adipose tissue and serum non-esterified fatty acids (NEFAs) in 125 volunteers stratified by PNPLA3 genotype (I148M carriers vs. non-carriers).
• Measurement of adipose tissue and liver PNPLA3 mRNA and protein levels.
• Assessment of whole-body insulin sensitivity of lipolysis using stable isotope tracers.

Main Results:

• PNPLA3-I148M carriers exhibited significantly increased PUFA-TGs in adipose tissue.
• PNPLA3 protein levels were substantially higher in adipose tissue than in the liver, both per tissue weight and relative to total body mass.
• The PNPLA3-I148M variant did not alter lipolysis rates or the composition of fasting serum NEFAs.

Conclusions:

• Contrary to prior assumptions, PNPLA3 is highly abundant in human adipose tissue.
• The PNPLA3-I148M variant locally remodels adipose tissue triglycerides to become polyunsaturated, similar to its effect in the liver.
• Alterations in adipose tissue metabolism due to PNPLA3-I148M do not appear to contribute to NAFLD development in carriers.