Chronic ethanol consumption plus an atherogenic diet cause metabolic steatohepatitis with advanced liver fibrosis in apolipoprotein E/low‐density lipoprotein receptor double‐knockout mice.

Background: Nonalcoholic steatohepatitis is the inflammatory subtype of nonalcoholic fatty liver disease with a high risk of progression to liver fibrosis. We investigated metabolic steatohepatitis with advanced liver fibrosis in apolipoprotein E/low‐density lipoprotein receptor double‐knockout (AL) mice fed a co‐diet of ethanol with a low‐carbohydrate–high‐protein‐high‐fat atherogenic diet (AD) for 16 weeks. We also examined the underlying mechanisms, especially hepatic sympathetic activation, involved in the effects. Methods: We maintained 12‐week‐old male AL mice on AD and a standard chow diet (SCD) with or without ethanol treatment for 16 weeks. Age‐matched male C57BL/6J mice on SCD without ethanol treatment served as controls. We conducted blood biochemical, histopathological, and fluorescence immunohistochemical, and reverse transcriptase polymerase chain reaction studies. Results: AL mice showed significant hyperlipidemia. AD induced increased body weight, hepatic steatosis, and hepatic damage; ethanol and the AD co‐diet resulted in hepatic sympathetic activation accompanied by hepatic steatosis, lobular inflammation, bridging fibrosis, and hepatic damage. Hepatic Kupffer cells (KCs) and hepatic stellate cells (HSCs), which showed sympathetic activation, produced 4.4‐ to 9.4‐fold more inflammatory factors (KC and KC‐derived tumor necrosis factor‐α, and chemokine [C‐C motif] ligand 2) and 2.0‐ to 32.0‐fold more fibrosis factors (HSC and HSC‐derived transforming growth factor β1 and collagen 1a1); all p < 0.05 vs. controls. Conclusions: We created a model of metabolic steatohepatitis with advanced liver fibrosis from coexisting hyperlipidemia and hepatic sympathetic activation in AL mice on a co‐diet of ethanol and AD. KCs and HSCs became the cellular targets of hepatic sympathetic activation, which could play a role in the initiation and progression of metabolic steatohepatitis with advanced liver fibrosis. [ABSTRACT FROM AUTHOR]