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.
Highlights
It is well recognized that consumption of diet containing high level of fat or alcohol induces fatty liver disease through multiple mechanisms [1] including microbiota and gut-liver axis [2,3]
We found that Camp–/– mice are protected against HFDEinduced liver fat accumulation and liver injury through suppressing hepatic neutrophil infiltration, increasing adipose lipolysis and enhancing fibroblast growth factor 21 (FGF21)/adiponectin production
Phosphorylation of hormone-sensitive lipase (HSL) was markedly reduced by high-fat diet plus alcohol (HFDE) in WT mice, and this reduction was observed in KO mice but to a much lesser extent (Figure 5A). These results suggested increased adipose tissue lipolysis when Cathelicidin-related antimicrobial peptide (CRAMP) is depleted, which could contribute to the attenuated adipocyte hypertrophy observed in HFDE fed Camp–/– mice, while at the same time possibly leading to increased circulating free fatty acids (FFA)
Summary
It is well recognized that consumption of diet containing high level of fat or alcohol induces fatty liver disease through multiple mechanisms [1] including microbiota and gut-liver axis [2,3]. Consumption of high-fat diet (HFD) and alcohol binge drinking synergistically induces fat deposition and inflammation in the liver [4,5]. The role of CRAMP in HFDor alcohol-induced fatty liver disease has been studied. A recent study showed that feeding wild type mice with short- or long-term HFD plus a single binge ethanol synergistically upregulated chemokine CXCL1 expression, elevated free fatty acid levels in both serum and liver, increased neutrophil infiltration in the liver, eventually leading to exacerbated liver injury [14]. The role of CRAMP in HFD plus binge ethanol-induced liver injury is unknown
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