FATTY-ACID METABOLISM AND THE PATHOGENESIS OF HEPATOCELLULAR-CARCINOMA - REVIEW AND HYPOTHESIS

Despite increasing understanding of the genetic control of cell growth and the identification of several involved chemical and infectious fa ctors, the pathogenesis of clinical and experimental hepatocellular ca rcinoma remains unknown. Available evidence is consistent with the pos sibility that selected changes in the hepatocellular metabolism of lon g-chain fatty acids may contribute significantly to this process. Spec ifically, studies of the peroxisome proliferators, a diverse group of xenobiotics that includes the fibrate class of hypolipidemic drugs, su ggest that increased fatty acid oxidation by way of extramitochondrial pathways (i.e., omega-oxidation in the smooth endoplasmic reticulum a nd beta-oxidation in the peroxisomes) results in a corresponding incre ase in the generation of hydrogen peroxide and, thus, oxidative stress . This in turn leads to alterations in gene expression and in DNA itse lf. We also review evidence supporting a potentially decisive influenc e of particular aspects of hepatocellular fatty acid metabolism in det ermining the activity of the extramitochondrial pathways. Moreover, ce rtain intermediates of extramitochondrial fatty acid oxidation (e.g., the long-chain dicarboxylic fatty acids) impair mitochondrial function and are implicated as modulators of gene expression through their int eraction with the peroxisome proliferator-activated receptor. Finally, the occurrence of hepatic tumors in type I glycogen storage disease ( glucose-6-phosphatase deficiency) may exemplify this general mechanism , which may also contribute to nonneoplastic liver injury and to tumor igenesis in other tissues.