We examined whether relative concentrations of circulating triacylglycerols (TAGs) between carriers compared with noncarriers of PNPLA3 I148M gene variant display deficiency of TAGs, which accumulate in the liver because of defective lipase activity. We also analyzed the effects of obesity-associated nonalcoholic fatty liver disease (NAFLD) independent of genotype, and of NAFLD due to either PNPLA3 I148M gene variant or obesity on circulating TAGs. A total of 372 subjects were divided into groups based on PNPLA3 genotype or obesity. Absolute and relative deficiency of distinct circulating TAGs was observed in the PNPLA3 148MM/148MI compared with the PNPLA3 148II group. Obese and 'nonobese' groups had similar PNPLA3 genotypes, but the obese subjects were insulinresistant. Liver fat was similarly increased in obese and PNPLA3 148MM/148MI groups. Relative concentrations of TAGs in the obese subjects versus nonobese displayed multiple changes. These closely resembled those between obese subjects with NAFLD but without PNPLA3 I148M versus those with the I148M variant and NAFLD. The etiology of NAFLD influences circulating TAG profiles. 'PNPLA3 NAFLD' is associated with a relative deficiency of TAGs, supporting the idea that the I148M variant impedes intrahepatocellular lipolysis rather than stimulates TAG synthesis. 'Obese NAFLD' is associated with multiple changes in TAGs, which can be attributed to obesity/insulin resistance rather than increased liver fat content per se.

Key Clinical MessageGitelman syndrome is an autosomal recessive disease mostly associated with loss‐of‐function mutations of the SLC12A3 gene and featured by clinical hypokalemia, hypomagnesemia, hypocalciuria, and histologically hypertrophy of the juxtaglomerular apparatus. A novel homozygous mutation (p.Arg399Pro) at the extracellular domain of SLC12A3 was found and correlated with the severe clinical manifestations.

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