1574-P: Catecholamine-Induced Adipose Lipolysis Drives Hepatic Steatosis in Pnpla3^I148M Knockin Mice

PNPLA3 (Patatin like phospholipid domain containing protein 3) I148M is the most common human genetic mutation associated with hepatic steatosis. Alterations in white adipose tissue (WAT) function are often linked to hepatic lipid accumulation, but current understanding of the effect of PNPLA3^I148M on WAT function is limited to the finding that this mutation does not appear to impact WAT insulin responsiveness. We evaluated WAT catecholamine responsiveness using the β3-adrenergic agonist CL 316243 (CL) in Pnpla3^I148M mice. In vivo, the plasma NEFA response to CL was increased in mutant mice (Basal NEFA: WT 0.65 ± 0.07 mM, MUT 0.66 ± 0.07 mM, P = 0.5; CL stimulated NEFA: WT 1.3 ± 0.1 mM, MUT 1.6 ± 0.1 mM, P = 0.03). Ex vivo, CL-induced fatty acid release from gonadal WAT was increased in mutant mice (1.22-fold increased NEFA release, P = 0.03). High sucrose diet fed Pnpla3^I148M mice are a known model of increased hepatic steatosis; beta adrenergic blockade with propranolol did not alter hepatic triglyceride content in WT mice as compared with vehicle, but markedly decreased hepatic triglyceride in Pnpla3^I148M mice (WT: VEH 37 ± 5 mg/g; PRO 36 ± 6 mg/g. MUT: VEH 55 ± 6 mg/g; PRO 19 ± 4mg/g, P = 0.0002). Acipimox, an inhibitor of WAT lipolysis, similarly had no effect on WT hepatic steatosis and markedly decreased hepatic triglyceride in Pnpla3^I148M mice (WT: VEH 46 ± 5 mg/g; ACI 49 ± 10 mg/g. MUT: VEH 78 ± 11 mg/g; ACI 40 ± 5mg/g, P = 0.006).

Conclusions: WAT catecholamine responsiveness is increased in Pnpla3^I148M mice contributing to hepatic steatosis in these mice. As human hepatic triglyceride biosynthesis is strongly weighted towards esterification of preformed fatty acids from extrahepatic sources, this biology may contribute to the increased susceptibility to fatty liver seen in patients with the PNPLA3^I148M mutation.