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 factors, the pathogenesis of clinical and experimental hepatocellular carcinoma remains unknown. Available evidence is consistent with the possibility that selected changes in the hepatocellular metabolism of long-chain fatty acids may contribute significantly to this, process. Specifically, studies of the peroxisome proliferators, a diverse group of xenobiotics that includes the fibrate class of hypolipidemic drugs, suggest that increased fatty acid oxidation by way of extramitochondrial pathways (i.e., omega-oxidation in the smooth endoplasmic reticulum and beta-oxidation in the peroxisomes) results in a corresponding increase in the generation of hydrogen peroxide and, thus, oxidative stress. This in turn leads to alterations in gene expression and in DNA itself. We also review evidence supporting a potentially decisive influence of particular aspects of hepatocellular fatty acid metabolism in determining the activity of the extramitochondrial pathways. Moreover, certain 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 interaction 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 tumorigenesis in other tissues.
Department of Medicine, University of California, San Francisco 94143-0630.
R K
RK
Ockner
R M
RM
Kaikaus
N M
NM
Bass
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000503:physiopathology*; D005227:Fatty Acids / Q000378:metabolism*; D005953:Glycogen Storage Disease Type I / Q000503:physiopathology; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000473:pathology / Q000503:physiopathology*; D008830:Microbodies / Q000502:physiology; D008954:Models, Biological; D010084:Oxidation-Reduction
D005227:Fatty Acids