Alcohol Activates TGF-Beta but Inhibits BMP Receptor-Mediated Smad Signaling and Smad4 Binding to Hepcidin Promoter in the Liver

Abstract

Hepcidin, a key regulator of iron metabolism, is activated by bone morphogenetic proteins (BMPs). Mice pair-fed with regular and ethanol-containing L. De Carli diets were employed to study the effect of alcohol on BMP signaling and hepcidin transcription in the liver. Alcohol induced steatosis and TGF-beta expression. Liver BMP2, but not BMP4 or BMP6, expression was significantly elevated. Despite increased BMP expression, the BMP receptor, and transcription factors, Smad1 and Smad5, were not activated. In contrast, alcohol stimulated Smad2 phosphorylation. However, Smad4 DNA-binding activity and the binding of Smad4 to hepcidin promoter were attenuated. In summary, alcohol stimulates TGF-beta and BMP2 expression, and Smad2 phosphorylation but inhibits BMP receptor, and Smad1 and Smad5 activation. Smad signaling pathway in the liver may therefore be involved in the regulation of hepcidin transcription and iron metabolism by alcohol. These findings may help to further understand the mechanisms of alcohol and iron-induced liver injury.

Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease

“…As described in the introduction section, expression of BMP2 and BMP4 has been reported in acute liver injury 6. Furthermore, BMP2, but not BMP4 or BMP6, expression was found to be significantly elevated in a model of chronic alcohol feeding in mice 31. Together, these data indicate that increased hepatic BMP6 expression in NAFLD results from hepatocellular lipid accumulation independent of liver inflammation and injury.…”

Neonatal binge alcohol exposure increases microglial activation in the developing rat hippocampus

“…Following an insult, TGF-β can reduce production of pro-inflammatory cytokines such as IL-2 and proliferation of T helper immune cells (Su et al, 2012). TGF-β is increased in the liver during alcohol-induced hepatic disease (Meyer et al, 2010; Gerjevic et al, 2012), but its role in the brain’s response to alcohol exposure has yet to be fully investigated. Recent work from the Valenzeula group (Topper et al, 2015) found no changes to TGF-β in the hippocampus and cerebellum of rats exposed to alcohol vapor during the neonatal period, possibly indicating an influence of route of administration or timing of analysis on the anti-inflammatory response.…”

Molecular mechanisms of ethanol-associated oro-esophageal squamous cell carcinoma

“…TGFβ signaling is inhibited by ethanol in rat cerebral cortex [154]. However, TGFβ is activated by ethanol in mouse liver and rat alveolar macrophage [155,156]. Meanwhile, exposure to ethanol increases fibroblast contraction, which is reduced by TGFβ inhibition [157].…”