Deficiency of Cathelicidin Attenuates High-Fat Diet Plus Alcohol-Induced Liver Injury through FGF21/Adiponectin Regulation

Abstract

Alcohol consumption and obesity are known risk factors of steatohepatitis. Here, we report that the deficiency of CRAMP (cathelicidin-related antimicrobial peptide—gene name: Camp) is protective against a high-fat diet (HFD) plus acute alcohol (HFDE)-induced liver injury. HFDE markedly induced liver injury and steatosis in WT mice, which were attenuated in Camp–/– mice. Neutrophil infiltration was lessened in the liver of Camp–/– mice. HFDE feeding dramatically increased epididymal white adipose tissue (eWAT) mass and induced adipocyte hypertrophy in WT mice, whereas these effects were attenuated by the deletion of Camp. Furthermore, Camp–/– mice had significantly increased eWAT lipolysis, evidenced by up-regulated expression of lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL). The depletion of Camp also increased uncoupling protein 1 (UCP1)-dependent thermogenesis in the brown adipose tissue (BAT) of mice. HFDE fed Camp–/– mice had elevated protein levels of fibroblast growth factor 21 (FGF21) in the eWAT, with an increased adiponectin production, which had been shown to alleviate hepatic fat deposition and inflammation. Collectively, we have demonstrated that Camp–/– mice are protected against HFD plus alcohol-induced liver injury and steatosis through FGF21/adiponectin regulation. Targeting CRAMP could be an effective approach for prevention/treatment of high-fat diet plus alcohol consumption-induced steatohepatitis.

The crosstalk between fibroblast growth factor 21 (FGF21) system and substance use

“…found that after a high-fat diet and one-week binge alcohol gavage, mice lacking cathelicidin-related antimicrobial peptide (CRAMP), an antimicrobial peptide that helps maintain a balanced microbiota, compared to wild-type mice, had elevated FGF21 levels in epididymal white adipose (eWAT) mass and increased serum adiponectin secretion, which has been shown to alleviate hepatic fat deposition and inflammation. 84 Given that after alcohol exposure, hepatic Camp mRNA significantly increased in WT mice, 85 which has been associated with increased reactive oxygen species production, and that FGF21 inhibits oxidative stress through cAMP response element binding protein (CREB) activation, 86 which regulates adiponectin gene expression, 87 a working hypothesis is that CRAMP deficiency upregulates FGF21/CREB/adiponectin signaling to limit alcohol-induced oxidative stress.…”

Advancements in the Alcohol-Associated Liver Disease Model

“…In previous decades, the development of ALD animal models allowed for significant progress to be made in ALD research [ 13 ]. Different ALD models can be used to study the pathogenesis of ALD at different stages [ 135 , 140 , 200 , 201 ]. However, by comparing different ALD models, we found that in models only using an LDE diet, the main changes in animals were limited to early ALD (hepatic steatosis and inflammation), while those of more severe ALD (such as hepatitis and fibrosis) were rarely able to be observed [ 112 ].…”

Fibroblast growth factor 21: An emerging pleiotropic regulator of lipid metabolism and the metabolic network

“… 176 Similar studies found that FGF21-adiponectin signaling regulates hepatic lipid metabolism, reducing steatohepatitis and the enrichment of inflammatory pathways in high-fat and acute-alcohol-induced liver injury mice. 177 A striking increase in very low-density lipoprotein receptor (VLDLR) can be an indicator of moderate and serious NAFLD, accompanied by endoplasmic reticulum stress. FGF21 protects against serious NAFLD by modulating VLDLR activity by governing endoplasmic reticulum stress.…”