Adiponectin in nonalcoholic fatty liver disease : correlation with liver damage and PNPLA3 genotype

Background&Aims : Adipose tissue insulin resistance plays a major contribution in the pathogenesis of NAFLD by increasing the release of free fatty acids (FFAs) and altering adipokines, in particular adiponectin. Recently, the patatin-like phospholipase domain-containing 3 (PNPLA3) I148M polymorphism has been demonstrated to influence susceptibility to NAFLD and the progression of liver damage in affected subjects. The mechanism is still not completely defined, but it might involve altered function of adipocytes. Aim was to assess the relationship between FFAs, adiponectin, and NAFLD, and to evaluate whether PNPLA3 genotype influences fasting levels of FFAs and adiponectin. Patients&Methods: We considered 144 consecutive Italian patients with NAFLD (115 with biopsy performed for persistently altered liver enzymes) and 68 healthy controls. The rs738409 PNPLA3 genotype (encoding for I148M) was evaluated by a Taqman assay, adiponectin by ELISA (Assaypro), and FFAs by an enzymatic assay. Results: The presence of NAFLD was significantly associated with FFAs (OR 1.013, 95% c.i. 1.01-1.02; p<0.0001), and adiponectin (OR 0.870, 95% c.i. 0.79-0.95; p=0.003), independently of age, sex, BMI, glucose, and insulin. In biopsied patients, adiponectin, but not FFAs, levels were significantly associated with a reduced risk of moderate/severe steatosis (OR 0.83, 95% c.i. 0.72-0.96; p=0.012), NASH (OR 0.86, 0.75-0.98, p=0.025), and of the presence of fibrosis (OR 0.84, 0.74-0.95; p=0.006) independently of age, sex, BMI, ALT, insulin, glucose levels, and FFAs. As expected, the 148M PNPLA3 variant was associated with NAFLD and NASH (p<0.0001). At ordinal logistic regression analysis, the PNPLA3 148M variant was associated with low adiponectin levels (<6mcg/ml), independently of gender, presence of diabetes, ALT levels, and dyslipidemia (tryglicerides/HDL ratio) both in patients (OR 0.10, 95% c.i. 0.01-0.19, p=0.03), and in the whole series of patients and controls (OR 0.11, 95% c.i. 0.04-0.19, p=0.03), but not with fasting FFAs or insulin levels. Conclusions: Modulation of the release of adiponectin, a molecule with insulin sensitizing, antiinflammatory, and anti-fibrotic activity, associated with the risk of NAFLD, NASH and progressive liver damage, may be involved in mediating the usceptibility to steatosis and NASH in carriers of the 148M PNPLA3 variant. We are currently seeking independent replication of the association between PNPLA3 genotype and adiponectin levels in a larger series of healthy subjects and in patients with viral hepatitis