Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders ranging from hepatic steatosis [excessive accumulation of triglycerides (TG)] to nonalcoholic steatohepatitis, which can progress to cirrhosis and hepatocellular carcinoma. The molecular pathogenesis of steatosis and progression to more severe NAFLD remains unclear. Obesity and aging, two principal risk factors for NAFLD, are associated with a hyperadrenergic state. b-Adrenergic responsiveness in liver increases in animal models of obesity and aging, and in both is linked to increased hepatic expression of b2-adrenergic receptors (b2-ARs). We previously showed that in aging rodents intracellular signaling from elevated hepatic levels of b2-ARs may contribute to liver steatosis. In this study we demonstrate that injection of formoterol, a highly selective b2-AR agonist, to mice acutely results in hepatic TG accumulation. Further, we have sought to define the intrahepatic mechanisms underlying b2-AR mediated steatosis by investigating changes in hepatic expression and cellular localization of enzymes, transcription factors, and coactivators involved in processes of lipid accrual and disposition—and also functional aspects thereof—in livers of formoterol-treated animals. Our results suggest that b2-AR activation by formoterol leads to increased hepatic TG synthesis and de novo lipogenesis, increased but incomplete b-oxidation of fatty acids with accumulation of potentially toxic long-chain acylcarnitine intermediates, and reduced TG secretion—all previously invoked as contributors to fatty liver disease. Experiments are ongoing to determine whether sustained activation of hepatic b2-AR signaling by formoterol might be utilized to model fatty liver changes occurring in hyperadrenergic states of obesity and aging, and thereby identify novel molecular targets for the prevention or treatment of NAFLD.
|Original language||English (US)|
|Journal||American Journal of Physiology - Endocrinology and Metabolism|
|State||Published - Jul 2021|
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Physiology (medical)