Abstract
The autonomic nervous system, consisting of sympathetic and parasympathetic branches, plays an important role in regulating metabolic homeostasis. The sympathetic nervous system (SNS) regulates hepatic lipid metabolism by regulating adrenergic receptor activation, resulting in the stimulation of hepatic very-low-density lipoprotein-triglyceride (TG) production in vivo. However, only a few studies on the relationship between SNS and hepatic steatosis have been reported. Here, we investigate the effect of adrenergic receptor agonists on hepatic steatosis in mice fed a high-fat diet (HFD). The α-adrenergic receptor agonist phenylephrine (10 mg/kg/d) or the β-adrenergic receptor agonist isoproterenol (30 mg/kg/d) was coadministered with HFD to male mice. After five weeks, hepatic steatosis, TG levels, and hepatic fat metabolism-related biomarkers were examined. HFD treatment induced hepatic steatosis, and cotreatment with phenylephrine, but not isoproterenol, attenuated this effect. Phenylephrine administration upregulated the mRNA levels of hepatic peroxisome proliferator-activated receptor alpha and its target genes (such as carnitine palmitoyltransferase 1) and increased hepatic β-hydroxybutyrate levels. Additionally, phenylephrine treatment increased the expression of the autophagosomal marker LC3-II but decreased that of p62, which is selectively degraded during autophagy. These results indicate that phenylephrine inhibits hepatic steatosis through stimulation of β-oxidation and autophagy in the liver.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome and metabolic comorbidities associated with obesity, type 2 diabetes, hyperlipidemia, and hypertension [1]
high-fat diet (HFD)-fed mice had a higher subepididymal fat weight than control mice; this weight was further increased by phenylephrine treatment but decreased by isoproterenol treatment (Table 1)
HFD treatment significantly increased the mRNA levels of hepatic sterol regulatory element-binding transcription factor 1 (SREBF1) and fatty acid synthase (FASN; Figure 2a,b) but did not change those of hepatic microsomal triglyceride transfer protein (MTTP), apolipoprotein B (ApoB), peroxisome proliferator-activated receptor alpha (PPARα), carnitine palmitoyltransferase 1 (CPT1), and acyl-coenzyme A oxidase 1 (ACOX1; Figure 2c–g)
Summary
Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome and metabolic comorbidities associated with obesity, type 2 diabetes, hyperlipidemia, and hypertension [1]. Regulates hepatic steatosis, which is involved in triglyceride (TG) metabolism by regulating the activation of adrenergic receptors. This activation results in the stimulation of hepatic very-low-density lipoprotein (VLDL)–TG production to increase plasma TG levels in vivo [5]. Previous reports have indicated that hepatic SNS activates the hepatic stellate cells involved in hepatic fibrosis [2]. Both α- and β-adrenergic receptor antagonists have been reported to affect liver injury models [8,9,10]. It remains to be elucidated whether adrenergic receptor agonists affect hepatic steatosis in NAFLD. We demonstrate that α-adrenergic receptor agonists, but not β-adrenergic receptor agonists, reduce steatosis in mice by stimulating fatty acid oxidation and autophagy in the liver
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