Nonalcoholic fatty liver disease: relationship to insulin sensitivity and oxidative stress. Treatment spproaches using vitamin E, magnesium, and betaine - Fatty Liver

Alternative Medicine Review, August, 2002 by Lyn Patrick

Both in animal models and human studies, hepatic mitochondria are the main source of oxidant stress. (33) Once mitochondrial reactive oxygen species are initiated they can further oxidize fat deposits, cause more lipid peroxidation, mitochondrial DNA damage, inhibit [beta]-oxidation, and create a continuing cycle of damage (Figure 2). This cycle involves mitochondrial damage, the release of pro-inflammatory cytokines, damage to Kupffer cells, and the constant consumption of antioxidant enzymes and vitamins in the liver. (37) The increased demand on antioxidant reserves is evident in the lower levels of plasma [alpha]-tocopherol seen in obese children when compared to nonobese children with similar dietary intakes of vitamin E. (38) Antioxidant levels and lipid peroxide levels have also been assessed in insulin resistance. In a study of 36 nondiabetic individuals, the more insulin resistant the patients were, the higher their levels of hydroperoxides. (39) Inversely, the more insulin resistance, the lower the plasma levels of carotenoids (or-carotene, [beta]-carotene, and lutein), [alpha]-tocopherol, [delta]-tocopherol. Plasma concentrations of several carotenoids and tocopherols were significantly related to elevated levels of hydroperoxides. The authors of this Stanford University study concluded that tocopherols and carotenoids should be acknowledged as "environmental factors" that modulate insulin effects. Other human studies also indicate that levels of lipophilic antioxidants may control insulin sensitivity. (40-43)

[FIGURE 2 OMITTED]

Other sources of oxidant stress in NASH are the cytochrome P450 enzymes CYP2E1 and CYP4A. Both are involved in the hydroxylation of fatty acids and the production of lipid peroxides when they are up-regulated. (44) CYP2E1 has been shown to be persistently up-regulated in type 2 diabetes, insulin resistance, central obesity, and NASH. (45) CYP2E1 is also up-regulated by a high-fat/low-carbohydrate diet. (44) Research in hepatic cell lines that over-express CYP2E1 have revealed the critical role antioxidants play in preventing hepatocyte injury in NASH. For example, lowering levels of reduced glutathione enhances the toxicity of arachidonic acid in CYP2E1-Over-expressing cells; however, that damage can be prevented by adding a range of antioxidants, including tocopherol. (44)

CYP2E1 may also play a role in hepatic fibrosis: oxidative stress resulting from up-regulation of this cytochrome has been shown to also up-regulate collagen I production in rat hepatic stellate cells, one of the initial steps in fibrosis. (46) This process was enhanced by glutathione depletion and reversed by antioxidants.

Other Potential Causes of NASH

There is evidence that bacterial endotoxins can induce steatohepatitis, through production of the cytokine tumor necrosis factor-alpha (TNF-[alpha]). (47) Bacterial endotoxin stimulates hepatic Kupffer cells and may lead to increased free radical production and hepatic steatosis and fibrosis. (48) Small intestinal bypass surgery is no longer a preferred treatment for morbid obesity due to the high incidence of steatohepatitis and cirrhosis that develop following this surgery. (49) Several patients have required liver transplantation after small intestinal bypass and NASH has returned in some individuals after transplant. The incidence of resulting hepatic failure was due to portal endotoxemia, a fatal complication of the surgery. The incidence of liver failure and steatohepatitis was reversed by the use of metronidazole therapy in these patients. The theory behind the reversal of NASH in these patients is that metronidazole eliminated a bacterial species producing endotoxin. Bacteroides is suspected by Lictman et al as the pathogen responsible for endotoxemia in these patients. (50)