James P. Hardwick, Ph.D. Lab
To understand the process of inflammation in human disease and the significance of fatty acid Omega hydroxylase genes (CYP4) in regulating inflammation and fatty acid metabolism.
James P. Hardwick, Ph.D., associate professor of biochemistry/molecular pathology
The cytochrome P450 gene 4 family (CYP4) consists of a group of over 63 members that function to ω-hydroxylate the terminal carbon of fatty acids. In mammals, six subfamilies have been identified and three of these subfamily members show a preference in the metabolism of short (C7-C10)-CYP4B, medium (C10-C16)-CYP4A, and long (C16-C26)-CYP4F, saturated, unsaturated and branched chain fatty acids. These ω-hydroxylated fatty acids are converted to dicarboxylic acids, which are preferentially metabolized by the peroxiosome β-oxidation system to shorter chain fatty acids that are transported to the mitochondria for complete oxidation or used either to supply energy for peripheral tissues during starvation or used in lipid synthesis.
The differential regulation of the CYP4A and CYP4F genes during fasting, by peroxisome proliferators and in non-alcoholic fatty liver disease (NAFLD) and hepatocarcinogenesis suggests different roles in lipid metabolism. The ω-hydroxylation and inactivation of pro-inflammatory eicosanoids by members of the CYP4F subfamily and the association of the CYP4F2 and CYP4F3 genes with inflammatory Celiac disease indicate an important role in the resolution of inflammation. The close clinical association of Celiac disease with inflammatory disease of the liver; primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, hemochromatosis, and fatty liver disease suggest that the CYP4 genes may play a vital functional role in the altered lipid metabolism and inflammation observed in these diseases.
Several human diseases have been genetically linked to the expression CYP4 gene polymorphic variants, which may link human susceptibility to diseases of lipid metabolism and the activation and resolution phases of inflammation. Understanding how the CYP4 genes are regulated during the fasting and feeding cycles and by endogenous lipids will provide therapeutic avenues in the treatment of metabolic disorders of lipid metabolism and inflammation.
My current research is directed toward understanding the control and regulation of the CYP4 genes in fatty liver disease and its progress to steatohepatitis and hepatocarcinogenesis. In fatty liver disease, we hypothesize that induction of the CYP4A genes and uncoupling of the catalytic cycle by excess fatty acids results in increase reactive oxygen species, which is the second hit in the progression of steatosis to steatohepatitis. In contrast, the down-regulation of the CYP4F genes in liver results in both a altered oleic to stearic acid ratio leading to increased fatty acid accumulation in hepatocytes (first hit) and increased pro-inflammatory LTB4 levels leading to neutrophil recruitment to liver (second hit).
Extending this hypothesis to the progression of liver steatohepatitis to hepatocarcinogensis is evident. Down-regulation of CYP4F genes, which metabolize arachidonic acid and pro-inflammatory leukotrienes that recruit immune cells to sites of injury allows transformed cells to escape the host immunosurveillance system and thereby have a selective growth advantage. CYP4F1 gene expression is elevated in hepatic tumors, and cytochrome P4504F1 metabolizes the potent chemokinetic and chemotactic modulator of the inflammatory response, LTB4. Therefore, tumor cells expressing P4504F1 escape the immunological surveillance system.