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/m2), 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/m2). 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

Keyword

dyslipidemia

insulin resistance

lipoproteins

metabolic syndrome

non-alcoholic fatty liver disease

patatin-like phospholipase domain containing 3

Publication and Content Type

art (subject category)

ref (subject category)