Synergistic Nutraceutical Effects of DLPC and SAMe

Summary

Principal Investigator: C S Lieber
Abstract: 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.
Funding Period: 2004-04-15 - 2008-03-31
more information: NIH RePORT

Top Publications

  1. ncbi DLPC and SAMe combined prevent leptin-stimulated TIMP-1 production in LX-2 human hepatic stellate cells by inhibiting HO-mediated signal transduction
    Qi Cao
    Alcohol Research and Treatment Center, Bronx Veterans Affairs Medical Center and Mount Sinai School of Medicine, Bronx, NY 10468, USA
    Liver Int 26:221-31. 2006
  2. ncbi Pathogenesis and treatment of alcoholic liver disease: progress over the last 50 years
    C S Lieber
    Alcohol Research and Treatment Center, Section of Liver Disease and Nutrition, Bronx VA Medical Center, New York 10468, USA
    Rocz Akad Med Bialymst 50:7-20. 2005
  3. ncbi DLPC and SAMe prevent alpha1(I) collagen mRNA up-regulation in human hepatic stellate cells, whether caused by leptin or menadione
    Qi Cao
    Alcohol Research and Treatment Center, James J Peters Veterans Affairs Medical Center, 130 W Kingsbridge Road, Bronx, NY 10468, USA
    Biochem Biophys Res Commun 350:50-5. 2006
  4. ncbi Beneficial effects versus toxicity of medium-chain triacylglycerols in rats with NASH
    Charles S Lieber
    Alcohol Research Center, James J Peters VA Medical Center, 130 West Kingsbridge Road 151 2, Bronx, NY 10468, USA
    J Hepatol 48:318-26. 2008

Scientific Experts

Detail Information

Publications5

  1. ncbi DLPC and SAMe combined prevent leptin-stimulated TIMP-1 production in LX-2 human hepatic stellate cells by inhibiting HO-mediated signal transduction
    Qi Cao
    Alcohol Research and Treatment Center, Bronx Veterans Affairs Medical Center and Mount Sinai School of Medicine, Bronx, NY 10468, USA
    Liver Int 26:221-31. 2006
    ..Because H2O2 mediates signal transduction-stimulating liver fibrogenesis, we investigated whether DLPC and SAMe attenuate the production of tissue inhibitor of metalloproteinase (TIMP)-1 by inhibiting H2O2 formation...
  2. ncbi Pathogenesis and treatment of alcoholic liver disease: progress over the last 50 years
    C S Lieber
    Alcohol Research and Treatment Center, Section of Liver Disease and Nutrition, Bronx VA Medical Center, New York 10468, USA
    Rocz Akad Med Bialymst 50:7-20. 2005
    ..Similarly dilinoleoylphosphatidylcholine (DLPC), PPC's main component, also partially opposes the increase in CYP2E1 by ethanol. Hence, therapy with SAMe +DLPC is now being considered...
  3. ncbi DLPC and SAMe prevent alpha1(I) collagen mRNA up-regulation in human hepatic stellate cells, whether caused by leptin or menadione
    Qi Cao
    Alcohol Research and Treatment Center, James J Peters Veterans Affairs Medical Center, 130 W Kingsbridge Road, Bronx, NY 10468, USA
    Biochem Biophys Res Commun 350:50-5. 2006
    ....
  4. ncbi Beneficial effects versus toxicity of medium-chain triacylglycerols in rats with NASH
    Charles S Lieber
    Alcohol Research Center, James J Peters VA Medical Center, 130 West Kingsbridge Road 151 2, Bronx, NY 10468, USA
    J Hepatol 48:318-26. 2008
    ..Because of the similarity of the pathogenesis of alcohol-induced liver damage and non-alcoholic steatohepatitis (NASH), our aim was to assess whether MCT is also beneficial in NASH...