β₂-Adrenergic Receptor Agonist Induced Hepatic Steatosis in Mice: Modeling Nonalcoholic Fatty Liver Disease in Hyperadrenergic States

Abstract

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. β-Adrenergic responsiveness in liver increases in animal models of obesity and aging, and in both is linked to increased hepatic expression of β2-adrenergic receptors (β2-ARs). We previously showed that in aging rodents intracellular signaling from elevated hepatic levels of β2-ARs may contribute to liver steatosis. In this study we demonstrate that injection of formoterol, a highly selective β2-AR agonist, to mice acutely results in hepatic TG accumulation. Further, we have sought to define the intrahepatic mechanisms underlying β2-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 β2-AR activation by formoterol leads to increased hepatic TG synthesis and de novo lipogenesis, increased but incomplete β-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 β2-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.

Reversible lysine fatty acylation of an anchoring protein mediates adipocyte adrenergic signaling

“…Enhancing gravin-α myristoylation could also lead to detrimental effects. For example, β 2 -AR signaling has been linked to dysregulation of hepatic lipid metabolism and may contribute to the development of nonalcoholic fatty liver disease ( 59 ). The availability of FT895, which has pharmacokinetic properties that are suitable for in vivo studies ( 27 ), should facilitate efforts to determine the constellation of potential therapeutic indications for HDAC11 inhibitors and could uncover untoward consequences of inhibiting this lysine demyristoylase.…”

Cannabis sativa L. (var. indica) Exhibits Hepatoprotective Effects by Modulating Hepatic Lipid Profile and Mitigating Gluconeogenesis and Cholinergic Dysfunction in Oxidative Hepatic Injury

“…CBD also showed a potent interaction with a binding energy of −8.7 kcal/mol and bound to TYR 308 and THR 110 residues of the human β2 adrenergic receptor (Table 2; Supplementary Figure S2). The β2 adrenergic receptor has been implicated in hepatotoxicity, as its activation has been linked to exacerbated hepatic TG, lipogenesis, and dysregulated fatty acid metabolism (Shi et al, 2021). The molecular interactions between the phytocannabinoids and the receptor may therefore indicate the potentials of CBD and Δ-9-THC to inactivate the β2 adrenergic receptor, thus modulating the adrenergic system.…”

Serine catabolism generates liver NADPH and supports hepatic lipogenesis

“…Here, however, we also used intravenous infusion. For animals with intravenous access, this allows delivery of a large volume of D 2 O in a temporally controlled manner without the animal handling (and potential associated stress-induced alterations in lipogenesis) associated with IP dosing 70 , 72 – 74 . The resulting increased deuterium labeling enabled label detection directly in NADPH, in addition to in fat 24 .…”