The Combination of S-adenosylmethionine and Dilinoleoylphosphatidylcholine Attenuates Non-alcoholic Steatohepatitis Produced in Rats by a High-Fat Diet.

In the pathogenesis of non-alcoholic steatohepatitis (NASH), oxidative stress resulting from free radicals generated by cytochrome P4502E1 (CYP2E1) plays a major role suggesting the importance of antioxidants. The objective of this study was to assess in a high-fat diet (HF) rat model the effects of the combination of s-adenosylmethionine (SAMe) plus dilinoleoylphosphatidylcholine (DLPC) in the treatment of NASH. To test the hypothesis that these two antioxidants are beneficial in NASH, male Sprague-Dawley rats were fed five different diets for six weeks: control, HF diet and HF plus SAMe and DLPC or their combination.

Leptin represses matrix metalloproteinase-1 gene expression in LX2 human hepatic stellate cells.

Background/aims: Collagen accumulation in liver fibrosis is due in part to decreased expression of matrix metalloproteinase (MMP)-1 relative to TIMP-1. LX-2 hepatic stellate cells produce increased amounts of collagen and tissue inhibitor of metalloproteinase (TIMP)-1 in response to leptin. The effect of leptin on MMP-1 production has not been reported.

DLPC and SAMe prevent alpha1(I) collagen mRNA up-regulation in human hepatic stellate cells, whether caused by leptin or menadione.

We previously reported that the combination of dilinoleoylphosphatidylcholine (DLPC) and S-adenosylmethionine (SAMe), which have antioxidant properties and antifibrogenic actions, prevented leptin-stimulated tissue inhibitor of metalloproteinase (TIMP)-1 production in hepatic stellate cells (HSCs) by inhibiting H2O2-mediated signal transduction. We now show that DLPC and SAMe inhibit alpha1(I) collagen mRNA expression induced by leptin or menadione in LX-2 human HSCs. We found that DLPC and SAMe prevent H2O2 generation and restore reduced glutathione (GSH) depletion whether caused by leptin or menadione.

Aspartate aminotransferase to platelet ratio index in patients with alcoholic liver fibrosis.

Objective: Aspartate aminotransferase (AST) to platelet ratio index (APRI) has been proposed as an easily determined and accurate noninvasive marker of liver fibrosis in chronic hepatitis C. To validate APRI in hepatitis C and to determine its usefulness in other liver diseases, we evaluated APRI in patients with liver fibrosis due to excessive alcohol consumption with or without viral hepatitis C.

Methods: A total of 1,308 subjects from two VA cooperative studies of alcoholic liver disease were evaluated.

DLPC and SAMe combined prevent leptin-stimulated TIMP-1 production in LX-2 human hepatic stellate cells by inhibiting HO-mediated signal transduction.

Background/aims: Both dilinoleoylphosphatidylcholine (DLPC) and S-adenosylmethionine (SAMe) have antioxidant properties and antifibrogenic actions. 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.

Methods: LX-2 human hepatic stellate cells were treated with leptin with or without DLPC, SAMe or various inhibitors.

Pathogenesis and treatment of alcoholic liver disease: progress over the last 50 years.

Fifty years ago the dogma prevailed that alcohol was not toxic to the liver and that alcoholic liver disease was exclusively a consequence of nutritional deficiencies. We showed, however, that liver pathology developed even in the absence of malnutrition. This toxicity of alcohol was linked to its metabolism via alcohol dehydrogenase which converts nicotinamide adenine dinucleotide (NAD) to nicotinamide adenine dinucleotide-reduced form (NADH) which contributes to hyperuricemia, hypoglycemia and hepatic steatosis by inhibiting lipid oxidation and promoting lipogenesis.

Leptin enhances alpha1(I) collagen gene expression in LX-2 human hepatic stellate cells through JAK-mediated H2O2-dependent MAPK pathways.

Leptin, a liver profibrogenic cytokine, induces oxidative stress in hepatic stellate cells (HSCs), with increased formation of the oxidant H2O2, which signals through p38 and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways, stimulating tissue inhibitor of metalloproteinase-1 production. Since oxidative stress is a pathogenic mechanism of liver fibrosis and activation of collagen gene is a marker of fibrogenesis, we evaluated the effects of leptin on collagen I expression. We report here that, in LX-2 human HSCs, leptin enhances the levels of alpha1(I) collagen mRNA, promoter activity and protein.

Acarbose attenuates experimental non-alcoholic steatohepatitis.

The alpha-glucosidase inhibitor acarbose is beneficial in the prevention of type 2 diabetes. To determine whether it attenuates the commonly associated non-alcoholic steatohepatitis (NASH), we used an experimental NASH model. Rats were fed ad libitum a nutritionally adequate high fat diet (71% of calories as fat) with or without acarbose (200 mg/1000 calories) for 3 weeks.

Alcohol and health: a drink a day won't keep the doctor away.

We should not advise patients to start drinking alcohol for its alleged cardiovascular benefits. The negative effects of alcohol are well established, and the evidence of alcohol's benefits comes mainly from epidemiologic studies that were not well controlled for other influences, such as lifestyle factors. Moreover, we have other means of lowering cardiovascular risk that are safe and proven.

Leptin stimulates tissue inhibitor of metalloproteinase-1 in human hepatic stellate cells: respective roles of the JAK/STAT and JAK-mediated H2O2-dependant MAPK pathways.

Leptin is recognized as a profibrogenic hormone in the liver, but the mechanisms involved have not been clarified. The tissue inhibitor of metalloproteinase (TIMP)-1, which acts through inhibition of collagen degradation, is synthesized by activated hepatic stellate cells (HSC) in response to fibrogenic substances. The capacity of leptin to induce TIMP-1 and its signaling molecules were investigated in a human HSC cell line, LX-2.

Lycopene attenuates alcoholic apoptosis in HepG2 cells expressing CYP2E1.

To test the hypothesis that ethanol-induced hepatic apoptosis is secondary to the oxidative stress generated by cytochrome P4502E1 (CYP2E1), we assessed the effects of the carotenoid lycopene, a potent antioxidant extracted from tomatoes, on oxidative stress and apoptosis in HepG2 cells overexpressing CYP2E1 (2E1 cells). These were exposed for 5 days to 100mM ethanol and 10 microM lycopene or an equal volume of placebo (vehicle). Ethanol significantly increased apoptosis measured by flow cytometry and by TUNEL assay.

Dilinoleoylphosphatidylcholine reproduces the antiapoptotic actions of polyenylphosphatidylcholine against ethanol-induced hepatocyte apoptosis.

Background: Polyenylphosphatidylcholine (PPC), a mixture of polyunsaturated phosphatidylcholines extracted from soybeans, attenuates hepatocyte apoptosis induced by ethanol feeding of rats. Our aims were to evaluate whether dilinoleoylphosphatidylcholine (DLPC), the main component of PPC, reproduces the antiapoptotic actions of PPC against alcohol-induced apoptosis and to identify the apoptotic proteins that are affected by PPC and DLPC.

Methods: Rats were fed Lieber-DeCarli liquid diets containing ethanol (35% of energy) or an isocaloric amount of carbohydrate for 4 weeks.

Lycopene attenuates arachidonic acid toxicity in HepG2 cells overexpressing CYP2E1.

Arachidonic acid (AA) was shown to be toxic to HepG2 cells expressing cytochrome P4502E1 (CYP2E1) because of oxidative stress. The aim of this study was to investigate whether lycopene, a carotenoid with high anti-oxidant capacity, protects HepG2 cells expressing CYP2E1 against AA toxicity. In preliminary experiments, lycopene as well as placebo (vehicle) were not toxic in the three types of cells tested: HepG2 cells, HepG2 cells transfected with pCI-neo (Neo) or pCI-neo/2E1 (2E1).

Dilinoleoylphosphatidylcholine decreases acetaldehyde-induced TNF-alpha generation in Kupffer cells of ethanol-fed rats.

We previously reported that dilinoleoylphosphatidylcholine (DLPC) decreases lipopolysaccharide-induced TNF-alpha generation by Kupffer cells of ethanol-fed rats by blocking p38, ERK1/2, and NF-kappaB activation. Here we show that DLPC also decreases TNF-alpha induction by acetaldehyde, a toxic metabolite released by ethanol oxidation. Acetaldehyde induces TNF-alpha generation with a maximal effect at 200 microM and activates p38 and ERK1/2; the latter in turn activates NF-kappaB.

DLPC decreases TGF-beta1-induced collagen mRNA by inhibiting p38 MAPK in hepatic stellate cells.

Dilinoleoylphosphatidylcholine (DLPC), the active component of polyenylphosphatidylcholine extracted from soybeans, decreases collagen accumulation induced by TGF-beta1 in cultured hepatic stellate cells (HSCs). Because DLPC exerts antioxidant effects and TGF-beta1 generates oxidative stress, we evaluated whether the antifibrogenic effect of DLPC is linked to its antioxidant action. In passage 1 culture of rat HSCs, TGF-beta1 induced a concentration-dependent increase in procollagen-alpha(1)(I) mRNA levels and enhanced intracellular H(2)O(2) and superoxide anion formation and lipid peroxidation but decreased GSH levels.

Dilinoleoylphosphatidylcholine decreases LPS-induced TNF-alpha generation in Kupffer cells of ethanol-fed rats: respective roles of MAPKs and NF-kappaB.

Activation of Kupffer cells by lipopolysaccharide (LPS) after ethanol feeding results in overproduction of TNF-alpha, leading to liver injury. Since dilinoleoylphosphatidylcholine (DLPC) protects against liver injury and has antioxidant properties, we investigated whether it alters LPS signaling leading to decreased TNF-alpha production. Kupffer cells were isolated from rats fed alcohol-containing or isocaloric control diets for 3 weeks.

Dilinoleoylphosphatidylcholine prevents transforming growth factor-beta1-mediated collagen accumulation in cultured rat hepatic stellate cells.

Polyenylphosphatidylcholine (PPC), a mixture of polyunsaturated phosphatidylcholines, protects against alcoholic and nonalcoholic liver fibrosis in baboons and rats, respectively. In this study, we assessed the antifibrogenic action of dilinoleoylphosphatidylcholine (DLPC), the main phosphatidylcholine species of PPC, against transforming growth factor-beta1-mediated expression of alpha1(I) procollagen, tissue inhibitor of metallopreoteinase-1 (TIMP-1) and matrix metalloproteinase-13 (MMP-13) in cultured rat hepatic stellate cells (HSCs). In primary culture-activated HSCs, TGF-beta1 up-regulated the alpha1(I) procollagen mRNA level with a concomitant increase in type I collagen accumulation in culture media.

Dilinoleoylphosphatidylcholine is responsible for the beneficial effects of polyenylphosphatidylcholine on ethanol-induced mitochondrial injury in rats.

Chronic ethanol consumption depletes phosphatidylcholines (PC) in membranes and hepatic mitochondria are an early target of this toxicity. Our previous studies showed that soybean-derived polyenylphosphatidylcholine (PPC), attenuated mitochondrial liver injury. Since dilinoleoylphosphatidylcholine (DLPC) is the major component of PPC, we assessed whether it is responsible for the protection of PPC.

Alcoholic liver injury: pathogenesis and therapy in 2001.

Much progress has been made in the understanding of the pathogenesis of alcoholic liver disease, resulting in improvement of prevention and promising prospects for even more effective treatments. It continues to be important to replenish nutritional deficiencies when present but it is crucial to recognize that, because of the alcohol-induced disease process, some of the nutritional requirements change. For instance, methionine, one of the essential amino acids for humans, must be activated to SAMe but, in severe liver disease, the activity of the corresponding enzyme is depressed.

Dilinoleoylphosphatidylcholine decreases ethanol-induced cytochrome P4502E1.

Cytochrome P4502E1 (CYP2E1) induction by ethanol contributes to alcoholic liver disease and we found that a mixture of polyunsaturated phosphatidylcholines (PPC), which protects against alcohol-induced liver injury, also decreases CYP2E1. Since dilinoleoylphosphatidylcholine (DLPC) is the major component of PPC, we assessed here whether it is responsible for the protection of PPC by feeding rats for 8 weeks our liquid diet containing ethanol (36% of energy) or isocaloric carbohydrates, with either DLPC (1.5 g/1000 cal), PPC (3 g/1000 cal), or linoleate.

Effect of beta-carotene on hepatic cytochrome P-450 in ethanol-fed rats.

Background: Hepatotoxicity of ethanol is increased by beta-carotene in both rodents and nonhuman primates. Furthermore, in smokers who are also drinkers, beta-carotene increases the incidence of pulmonary cancer. The hepatotoxicity was associated with proliferation of the membranes of the smooth endoplasmic reticulum, suggesting the involvement of cytochromes P-450.

Liver diseases by alcohol and hepatitis C: early detection and new insights in pathogenesis lead to improved treatment.

Much progress has been made in the understanding of the pathogenesis of alcoholic liver disease, resulting in improvement of treatment. Therapy must include correction of nutritional deficiencies, while taking into account changes of nutritional requirements. Methionine is normally activated to S-adenosylmethionine (SAMe).

Azide inhibits human cytochrome P -4502E1, 1A2, and 3A4.

Background: Recently, we showed that, in addition to cytochrome P-4502E1 (CYP2E1), CYP1A2 and CYP3A4 also contribute to the microsomal ethanol oxidizing system (MEOS). When MEOS activity is measured, sodium azide commonly is used to block the contaminating catalase. However, although CYP2E1 is considered insensitive to azide, its effect on the other P-450s is unknown.

Hepatic, metabolic, and nutritional disorders of alcoholism: from pathogenesis to therapy.

Much progress has been made in the understanding of the pathogenesis of alcoholic liver disease, resulting in an improvement in treatment. Nutritional deficiencies should be corrected when present but, because of the alcohol-induced disease process, some of the nutritional requirements change. For instance, methionine, one of the essential amino acids for humans, must be activated to S-adenosylmethionine (SAMe), but, in severe liver disease, the activity of the corresponding enzyme is depressed.

Dilinoleoylphosphatidylcholine protects human low density lipoproteins against oxidation.

LDL oxidation may promote atherosclerosis. We found that polyenyphosphatidylcholine (PPC), a mixture of polyunsaturated phospholipids extracted from soybeans, has antioxidant effects in in vivo models of oxidative stress. To assess whether components of PPC affect the in vitro oxidizability of LDL, plasma from 15 healthy volunteers was incubated with 10 microM of either dilinoleoyl-, palmitoyl-linoleoyl-, linoleoyl-palmitoyl- or distearoyl-phosphatidylcholine as well as 10 microM and 1 mM alpha-tocopherol.