The Pnpla3-I148m Variant Confers An Antiatherogenic Lipid Profile In Insulin-Resistant Patients

Context: The I148M (rs738409-G) variant in PNPLA3 increases liver fat content but may be protective against cardiovascular disease. Insulin resistance (IR) amplifies the effect of PNPLA3-I148M on liver fat.Objective: To study whether PNPLA3-I148M confers an antihyperlipidemic effect in insulin-resistant patients.Design: Cross-sectional study comparing the impact of PNPLA3-I148M on plasma lipids and lipoproteins in 2 cohorts, both divided into groups based on rs738409-G allele carrier status and median HOMA-IR.Setting: Tertiary referral center.Patients: A total of 298 obese patients who underwent a liver biopsy during bariatric surgery (bariatric cohort: age 49 +/- 9 years, body mass index [BMI] 43.2 +/- 6.8 kg/m(2)), and 345 less obese volunteers in whom liver fat was measured by proton magnetic resonance spectroscopy (nonbariatric cohort: age 45 +/- 14 years, BMI 29.7 +/- 5.7 kg/m(2)).Main Outcome Measures: Nuclear magnetic resonance profiling of plasma lipids, lipoprotein particle subclasses and their composition.Results: In both cohorts, individuals carrying the PNPLA3-I148M variant had significantly higher liver fat content than noncarriers. In insulin-resistant and homozygous carriers, PNPLA3-I148M exerted a distinct antihyperlipidemic effect with decreased very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) particles and their constituents, and increased high-density lipoprotein particles and their constituents, compared with noncarriers. VLDL particles were smaller and LDL particles larger in PNPLA3-I148M carriers. These changes were geometrically opposite to those due to IR. PNPLA3-I148M did not have a measurable effect in patients with lower IR, and its effect was smaller albeit still significant in the less obese than in the obese cohort.Conclusions: PNPLA3-I148M confers an antiatherogenic plasma lipid profile particularly in insulin-resistant individuals.