Rk. Ockner et al., FATTY-ACID METABOLISM AND THE PATHOGENESIS OF HEPATOCELLULAR-CARCINOMA - REVIEW AND HYPOTHESIS, Hepatology, 18(3), 1993, pp. 669-676
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.