Our long-term objective is to develop effective prevention and therapy for liver cirrhosis. One of its nutritional consequences is decreased enzymatic transformation of essential nutrients to their active form, including defective activation of methionine to s-adenosylmethionine (SAMe), with loss of many of methionine's vital functions. This deficiency responds only partially to SAMe supplementation because optimal [cellular function] also requires integrity of the membranes, which are injured by free radical attack on their phosphatidylcholine (PC) infrastructure. This can be overcome through phospholipid replenishment with dilinoleoylphosphatidylcholine (DLPC), a highly bioavailable PC, but SAMe is also required because it is a crucial co-factor in the regeneration of PC through methylation of phosphatidylethanolamine. A major cause of oxidative stress and liver injury is cytochrome P4502E1 (CYP2E1) when induced by either ethanol (in alcoholic liver disease), lipids (in obesity) and ketones (in diabetes). Available CYP2E1 inhibitors are too toxic for clinical use, except for DLPC recently discovered to inhibit CYP2E1. Our immediate aim is to test the synergistic effects of the administration of SAMe + DLPC, using rodent models of precirrhotic alcoholic and nonalcoholic steatohepatitis and CCI4-induced cirrhosis. Mechanisms of the beneficial interaction between SAMe and DLPC will be studied in vivo and also in vitro in cultured rodent hepatic stellate cells, Kupffer cells and macrophages, with focus on the preservation of the physiologic anti-oxidant glutathione, the restoration of phosphatidylethanolamine methyltransferase activity, the attenuation of oxidative stress and the resulting NF-?B activation, with lipid peroxidation and rise in the pathogenic cytokines TNF-?, TGF-?1, IL-1? and IL-6. Decreased fibrosis may be achieved through diminished stellate cell activation, enhanced collagenase activity and lowered leptin production. In summary, the synergistic effects of SAMe and DLPC, two innocuous and hepatoprotective nutraceuticals, will be tested against key modalities of experimental liver injury, including non-alcoholic and alcoholic steatohepatitis and CCI4 induced cirrhosis, thereby providing preclinical data needed to ultimately verify, in a clinical trial, the effectiveness of this nutraceutical combination in the prevention and treatment of liver cirrhosis, a common cause of mortality for which effective therapy is presently not available. ? ? ?
