Loss of hepatic alpha-1b adrenoceptor exacerbates inflammation and stellate cell activation in diet-induced MASLD

The brain regulates liver metabolism through neuroendocrine and autonomic pathways, which can be disrupted in metabolic dysfunction-associated steatotic liver disease (MASLD). Although autonomic dysfunction, including liver neuropathy, has been reported in MASLD, the role of hepatic sympathetic signaling in disease progression remains unclear. Recent studies show that liver innervation is predominantly of a sympathetic nature, suggesting that adrenergic receptors in hepatocytes may influence the pathogenesis of MASLD. We previously identified adrenoceptor alpha-1b (ADRA1B) as the dominant hepatic adrenergic receptor. Here, we hypothesized that ADRA1B plays a protective role in MASLD progression. To test this, we generated hepatocyte-specific <i>Adra1b</i> knockout mice (<i>Adra1b</i>^LKO) and induced MASLD with the Gubra Amylin NASH diet for up to 32 wk. Liver pathology was quantified by automated image analysis (MorphoQuant), and metabolic phenotyping included glucose tolerance, insulin sensitivity, and bile acid composition. Hepatocyte-specific <i>Adra1b</i> deletion did not affect body weight, hepatic lipid accumulation, glucose tolerance, or insulin sensitivity. However, <i>Adra1b</i>^LKO mice exhibited significantly increased hepatic inflammation compared to wild-type controls. These changes were associated with higher hepatic expression of tumor necrosis factor (<i>Tnf</i>) and interleukin-1b (<i>Il1b</i>), as well as an increase in monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6). We also observed elevated transforming growth factor beta (TGF-β) and α-smooth muscle actin (<i>Acta2</i>) expression, suggesting activation of hepatic stellate cells. In addition, <i>Adra1b</i>^LKO mice displayed higher circulating bilirubin levels, with no significant alterations in albumin and bile acid pool composition. These findings reveal a previously unrecognized role for hepatic ADRA1B in restraining inflammatory responses in MASLD. Loss of <i>Adra1b</i> signaling promotes hepatic inflammation, highlighting a neuroimmune mechanism that may be targeted to prevent disease progression.<b>NEW & NOTEWORTHY</b> This study identifies the hepatic α1b adrenoceptor (ADRA1B) as a regulator of inflammation in metabolic dysfunction-associated steatotic liver disease (MASLD). Using a hepatocyte-specific knockout model, we show that loss of <i>Adra1b</i> exacerbates hepatic inflammatory responses without affecting steatosis or systemic metabolism. These findings reveal a previously unknown immune mechanism in liver disease progression.