Brown adipose tissue inactivation exacerbates alcohol-induced liver steatosis, inflammation, and fibrosis.

Abstract

Alcohol-induced liver fibrosis is a devastating manifestation of alcohol-related liver disease (ALD). However, conventional mouse models fail to recapitulate this fibrotic phenotype, limiting their translational relevance. Mice develop and retain robust brown adipose tissue (BAT) for thermoregulation, which confers protection against hepatic steatosis. Here, we identify BAT as a key protective tissue against alcohol-induced liver fibrosis in mice. BAT was inactivated in mice via denervation or surgically ablated, followed by 8 wk of chronic plus binge alcohol exposure. Both BAT denervation and ablation markedly exacerbated hepatic steatosis, injury, and inflammation compared with sham controls. Remarkably, BAT inactivation or ablation induced robust hepatic stellate cell (HSC) activation and liver fibrosis in both sexes, as evidenced by increased α-smooth muscle actin expression, enhanced Sirius red and Masson's trichrome staining, and elevated hydroxyproline content. These fibrotic changes were absent in sham-operated controls. Mechanistically, BAT-conditioned medium-containing BAT-secreted batokines-induced lipid accumulation, oxidative stress, and cell injury in hepatocyte cultures. Furthermore, batokines directly targeted cultured macrophages and HSCs and suppressed their activities. Collectively, these results unveil a hepatoprotective role of BAT and batokines in ALD progression and establish a physiologically and translationally relevant mouse model of ALD by combining BAT inactivation with chronic plus binge alcohol exposure.Brown adipose tissue confers resistance to alcohol-related liver disease through secreting batokines. Inactivation of brown fat exacerbates alcohol-induced liver steatosis, inflammation, and fibrosis.