Fatty-acid metabolism and the pathogenesis of hepatocellular carcinoma: Review and hypothesis

Abstract

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.

Lipids changes in liver cancer

“…Available evidence (Ockner et al, 1993) is consistent with the possibility that selected changes in the hepatocellular metabolism of long-chain fatty acids may contribute significantly to this process, nonneoplastic liver injury, and tumorigenesis in other tissues.…”

“…Available evidence (Ockner et al, 1993) is consistent with the possibility that selected changes in the hepatocellular metabolism of long-chain fatty acids may contribute significantly to this process, which in turn leads to alterations in gene expression and in DNA itself. 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, which may also contribute to nonneoplastic liver injury and to tumorigenesis in other tissues.…”

Increased mitochondrial palmitoylcarnitine/carnitine countertransport by flavone causes oxidative stress and apoptosis in colon cancer cells

“…The anaerobic use of glucose as an energy source through glycolysis by the so-called 'Warburg effect' is a common feature of most tumors [22]. Moreover, cancer cell metabolism is also characterized by a low rate of fatty acid oxidation [22][23][24]. Although energy yield is low when substrates are not completely oxidized, these adaptations in rapidly growing cancer cells at the same time minimize ROS production and prevent DNA and proteins from being damaged by oxygen radicals when produced during oxidative phosphorylation [2].…”

Aberrant miR199a-5p/caveolin1/PPARα axis in hepatic steatosis

“…Accordingly, decreased mitochondrial FA b-oxidation has been considered to be one of the major mechanisms underlying the disturbances in lipid metabolism in liver and steatosis (Ockner et al 1993). Furthermore, results from studies of both animal models and humans showed that decreased mitochondrial FA b-oxidation is closely associated with mitochondrial dysfunction (Nassir & Ibdah 2014).…”