*Purpose: Nonalcoholic fatty liver disease (NAFLD) and associated non-alcoholic steatohepatitis (NASH) is a rising cause of end stage liver disease, increasing the need for liver transplantation. At the same time, NAFLD has led to worsened quality of organs available for transplantation. Therefore, a great deal of interest exists in not only treating liver fibrosis, but in improving these marginal organs for transplantation. CD38, a multifunctional ectoenzyme and modulator of intracellular calcium metabolism, has been associated with liver inflammation and some forms of liver fibrosis and may serve as a biomarker and a therapeutic target. Here, we investigate the expression of CD38 in a methionine choline deficient (MCD) fatty liver rat model. Further, we investigate the mechanism and contribution of CD38 activation to injury in this fatty liver model.

*Methods: The methionine choline deficient (MCD) diet has been previously identified as an inducer of fatty liver disease in rats. In this experiment, the MCD diet was fed to rats for 4 weeks and the fatty liver and inflammatory phenotype was confirmed by histology, measurements of plasma ALT and AST, plasma and liver tissue triglycerides (TG), and various inflammatory cytokines. CD38 expression and activity was determined in the liver tissue using qPCR, CD38 hydrolase and CD38 cyclase activity assays, and immunohistochemistry. CD38 expression and activity in major liver cell types was evaluated using flow cytometry and qPCR.

*Results: Four weeks of MCD diet led to increased ALT and AST levels in plasma, as well as increased TG and MDA levels in liver tissue. Additionally, MCD diet resulted in the increased expression of pro-inflammatory cytokines including TNF and CCL-2 and markers of liver fibrosis TGF-beta and MMP-9. These findings are consistent with a fatty and inflammatory liver profile as would be seen in NASH. MCD diet resulted in increased CD38 expression and activity, and the NAD/NADH ratio, as well as ATP, was significantly reduced in the fatty liver diet consistent with depletion cellular NAD pool. Additionally, MCD diet resulted in increase CD38 expression of surface and CD38 activity in hepatocytes, while expression in other cell types remained relatively constant in other liver cell types. Through further evaluation, it was noted that this increased expression is largely driven by a small population of small hepatocytes, which was significantly increased by the MCD diet.

*Conclusions: The study demonstrates that CD38 contributes to the pathophysiology of liver injury in marginal organs via depletion of NAD pools, a common pathway in advanced age livers, ischemia/reperfusion injury and steatosis (NAFLD). Additionally, we identified a population of small hepatocytes with high CD38 expression that are increased by MCD diet. Future studies will explore the role of these small hepatocyte population in liver inflammation, fibrosis and repair.

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