The relationship between conjugated linoleic acid (CLA), hepatic gene expression and hepatocarcinogenesis
Abstract
Conjugated linoleic acid (CLA, 18:2) refers to a class of positional and geometric isomers of octadecadienoate. CLA exerts various beneficial effects in experimental animals including anticancer, antiatherogenic and antidiabetogenic actions. The mechanisms remain elusive. Several isomers of CLA are potent ligands and activators of PPARα. Activators of PPARα are known to exert differential effects on PPAR-associated gene expression and lipid metabolism. Many agents that are activators of PPARα have been demonstrated to induce rodent liver cancer. The overall hypothesis of this dissertation is that the ubiquitous beneficial actions of dietary CLA in extrahepatic tissues are dependent upon its role in modulating fatty acid composition, metabolism and gene expression in the liver. Among several isomers of CLA, 9Z11E and 10E12Z are two of the most potent activators of PPARα. hPPARα6/29, a dominant-negative form of PPARα inhibits 9Z11E-CLA-induced PPARα activity in vitro. Insulin enhanced the activation of PPARα by CLA, while phosphatase inhibitors further increased the ability of CLA to activate PPARα dramatically. These data suggest that phosphorylation events are required for alterations in gene expression by CLA. CLA increased Δ6 desaturase mRNA level in vivo and in vitro. The Δ6 desaturase inhibitor, SC-26,196, can inhibit 9Z11E-CLA-induced activation of PPARα and PPARγ. Forced expression of anti-sense Δ6 desaturase significantly decreased the activation of PPARα (or PPARγ) by CLA. After initiation, Fischer 344 rats were placed on diets containing CLA (0.0%, 0.5%, 1.0%, or 1.5%) or Wy-14,643 (0.01%) diet for 50 days or 93 days. Six days prior to sampling, rats were implanted with osmotic minipumps containing BrdU to measure hepatic DNA synthesis. Rats fed CLA showed no difference in body weight or liver weight. Dietary CLA increased the mRNA levels of liver fatty acid binding protein and acyl-CoA oxidase. CLA diets significantly induced proliferation in normal hepatocytes and focal lesions. Incidence of apoptosis in normal surrounding areas of hepatocytes was increased in dietary CLA groups. This research will provide further insight into understanding the biological activity and broader health implications of CLA. In addition, these data will be helpful in determining the potential role of CLA in rodent hepatocarcinogenesis.
Degree
Ph.D.
Advisors
Belury, Purdue University.
Subject Area
Nutrition|Oncology
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