Healthy PNPLA3 Risk Allele Carriers Present with Unexpected Body Fat Composition. A Study of One ousand Subjects

Abstract

Introduction: The common PNPLA3 (adiponutrin) variant p.I148M represents a major genetic driver of progression in non-alcoholic fatty liver disease (NAFLD). NAFLD is commonly associated with traits of the metabolic syndrome, therefore it is mostly suspected in obese individuals. Here, we investigate the association between the PNPLA3 variant and anthropometric traits in a cohort of healthy individuals.Patients and methods: We recruited 1,000 (500 females; age 18 - 66 years) healthy blood donors. The PNPLA3 variant was genotyped using TaqMan assays. All individuals were phenotyped with respect to anthropometric characteristics. We also determined the percentage of total fat (F%) and active tissue (TA%) of body weight.Results: Healthy carriers of the PNPLA3 [IM] and [MM] genotypes, although not differing in height from individuals with the genotype [II], displayed significantly lower body weight and lower BMI (both P = 0.005), higher TA% (P = 0.03) but lower F% (P = 0.03) and smaller waist, chest and shin circumferences (all P < 0.05). Separate analysis for males and females demonstrated an association between the [IM] and [MM] genotypes and higher TA% but lower F% (P = 0.04) in females. In males, BMI and total weight were significantly (P = 0.04) lower among carriers of the [M] allele.Discussion: Healthy individuals carrying the prosteatotic PNPLA3 allele p.I48M may be leaner as compared to the carriers of the common allele. Hence in clinical practice they might be overlooked since they do not necessarily present with the anthropometric characteristics commonly associated with severe hepatic steatosis.Abbreviations: ATX - autotaxin; BMI - body mass index; F% - total fat of body weight in %; Fkg - total fat of body weight in kilograms; GWAS - genome-wide association study; LPA - lysophosphatidic acid; NAFLD, non-alcoholic fatty liver disease; NASH - non-alcoholic steatohepatitis; PA - phosphatidic acid; PNPLA3-patatin-like phospholipase domain containing 3 (adiponutrin); TA% - active tissue of body weight in %; TAkg - active tissue of body weight in kilograms; WHR - waist-to-hip ratio.

PNPLA3rs1010023 Predisposes Chronic Hepatitis B to Hepatic Steatosis but Improves Insulin Resistance and Glucose Metabolism

“…Thus, inverse correlation between peripheral lipid and insulin sensitivity may exhibit the mechanisms underlying the improvement of glycolipid metabolism [ 53 ]. Moreover, other risk SNPs (e.g., PNPLA3 rs139051) for NAFLD have recently been revealed to associate with reduced levels of BMI and IR [ 28 , 54 ].…”

Fatty Acid and Glucose Sensors in Hepatic Lipid Metabolism: Implications in NAFLD

“…Adipose tissue function is thus an important factor in the pathophysiology of NAFLD and its progression toward NASH as shown by the fact that loss of function of key genes in adipogenesis promotes steatosis and the progression of liver damage, [8][9][10] and variants in genes known to be associated to steatosis (e.g., PNPLA3) also affect AT distribution. 11 In health, AT protects the body from an excessive exposure to fatty acids; when adipocyte expandability is exhausted, this event is associated with lipotoxicity (the accumulation of toxic fatty acids derivatives in organs different from AT) and peripheral insulin resistance. Adipose tissue acquires a proinflammatory profile (suppression of adiponectin, promotion of adipocytokines) and these events in the liver lead to accumulation of lipid toxic species, reactive oxygen species (ROS) production, endoplasmic reticulum stress, activation of stellate cells, and progression of liver damage.…”