Possible role of CD38 in lipid homeostasis in the liver of CD-1 mice

Abstract

CD38 is a type II transmembrane ectoenzyme that utilizes NAD+ to produce cADPR and NAADP, both of which are calcium mobilizers. Although CD38 is present in significant levels in the plasma membranes as well as nuclear envelopes of hepatocytes, its functional roles in liver are still relatively unknown. Using CD38a??/a?? mouse model, it was shown that CD38 was the major ADP-ribosyl cyclase in the liver. The expression of Cyp4a10 and 4a14 transcripts was upregulated in CD38a??/a?? mice whereas no significant change was noted in the Cyp4a12 transcript. This induction correlated with its respective protein levels and CYP4A enzymatic activities. However, other members of CYP450s subfamilies (Cyp1a2, 2b10, 2d9, 2e1 and 3a11) remained unchanged. Additionally, hepatic microsomal lipid peroxidation was also elevated in CD38a??/a?? mice, which suggested that ROS generated from CYP4A-mediated fatty oxidation might cause oxidative stress in CD38a??/a?? hepatocytes. One novel finding was that there was an excessive amount of lipid deposits in the livers of CD38a??/a?? mice. Concordant with this, these mice had higher hepatic triglyceride level but similar cholesterol level compared to control wild-type mice. These changes corresponded to the expression of genes encoding enzymes involving in the synthesis of fatty acids such as the increased mRNA abundance of FAS and its transcription factor, SREBP-1c. In contrast with increased lipogenesis, expression of genes associated with mitochondrial and peroxisomal fatty acid I?-oxidation did not differ between CD38a??/a?? and CD38+/+ mice, suggesting that fatty acid I?-oxidation was probably not affected by CD38 gene disruption. In addition, triacylglycerol secretion pathway did not seem to be induced by the knockout of CD38. Taken together, these studies suggest a novel role of CD38 in hepatic lipid homeostasis.