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.

Alcohol alters hepatic FoxO1, p53, and mitochondrial SIRT5 deacetylation function.

Chronic alcohol consumption affects the gene expression of a NAD-dependent deacetylase Sirtuis 1 (SIRT1) and the peroxisome proliferator-activated receptor-gamma coactivator1alpha (PGC-1alpha). Our aim was to verify that it also alters the forkhead (FoxO1) and p53 transcription factor proteins, critical in the hepatic response to oxidative stress and regulated by SIRT1 through its deacetylating capacity. Accordingly, rats were pair-fed the Lieber-DeCarli alcohol-containing liquid diets for 28 days.

Effect of chronic alcohol consumption on Hepatic SIRT1 and PGC-1alpha in rats.

The nuclear genes, NAD-dependent deacetylase Sirtuis 1 (SIRT1) and the peroxisome proliferator-activated receptor-gamma coactivator1alpha (PGC-1alpha) are regulators of energy metabolism. Here, we studied the role of alcohol consumption in expression of these sensing molecules. Alcohol significantly reduced hepatic SIRT1 mRNA by 50% and PGC-1alpha mRNA by 46% and it significantly inhibited the protein expression of SIRT1 and PGC-1alpha, while the transcription factor PPAR-gamma remained unchanged.

Beneficial effects versus toxicity of medium-chain triacylglycerols in rats with NASH.

Background/aims: Replacing long-chain triacylglycerols (LCT) with medium-chain triacylglycerols (MCT) reduces alcohol-induced liver injury. 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.

Methods: We used a rat NASH model in which corn oil (35% of total calories) was isocalorically replaced with MCT.

Inflammation and repair in viral hepatitis C.

Hepatitis C viral infection (HCV) results in liver damage leading to inflammation and fibrosis of the liver and increasing rates of hepatic decompensation and hepatocellular carcinoma (HCC). However, the host's immune response and viral determinants of liver disease progression are poorly understood. This review will address the determinants of liver injury in chronic HCV infection and the risk factors leading to rapid disease progression.

Role of medium-chain triglycerides in the alcohol-mediated cytochrome P450 2E1 induction of mitochondria.

Background: Chronic alcohol consumption is known to induce cytochrome P450 2E1 (CYP2E1) leading to lipid peroxidation, mitochondrial dysfunction and hepatotoxicity. We showed that replacement of dietary long-chain triglycerides (LCT) by medium-chain triglycerides (MCT) could be protective. We now wondered whether the induction of mitochondrial CYP2E1 plays a role and whether liver injury could be avoided through mitochondrial intervention.

DLPC attenuates alcohol-induced cytotoxicity in HepG2 cells expressing CYP2E1.

Aims: Alcoholic liver injury was shown to result largely from oxidative stress generated by ethanol metabolism via cytochrome P4502E1 (CYP2E1). Our aim was to determine whether this could be overcome by using dilinoleoylphosphatidylcholine (DLPC), an innocuous antioxidant extracted from soybeans.

Methods: To address this question, we determined whether DLPC protects against alcohol-induced cytotoxicity in HepG2 cells expressing CYP2E1.

Model of nonalcoholic steatohepatitis.

Background: Obesity and diabetes are frequently associated with nonalcoholic steatohepatitis (NASH), but studies have been hampered by the absence of a suitable experimental model.

Objective: Our objective was to create a rat model of NASH.

Design: Sprague-Dawley rats were fed a high-fat, liquid diet (71% of energy from fat, 11% from carbohydrates, 18% from protein) or the standard Lieber-DeCarli diet (35% of energy from fat, 47% from carbohydrates, 18% from 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.

Gene expression profiling of alcoholic liver disease in the baboon (Papio hamadryas) and human liver.

The molecular pathogenesis of alcoholic liver disease (ALD) is not well understood. Gene expression profiling has the potential to identify new pathways and altered molecules in ALD. Gene expression profiles of ALD in a baboon model and humans were compared using DNA arrays.

Silymarin retards the progression of alcohol-induced hepatic fibrosis in baboons.

Unlabelled: GOAL/BACKGROUND: Hepatoprotective effects of silymarin in patients with alcoholic liver disease are controversial. For strict control, this was assessed in non-human primates. STUDY Twelve baboons were fed alcohol with or without silymarin for 3 years with a nutritionally adequate diet.

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.

Cytokeratin 7 staining of hepatocytes predicts progression to more severe fibrosis in alcohol-fed baboons.

Background/aims: Not all alcoholic patients develop severe liver disease with fibrosis progressing to cirrhosis. It is of practical importance to determine whether some markers can predict progression of liver fibrosis.

Methods: We used a baboon model that mimics human alcoholic liver disease.

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).

SMART amplification maintains representation of relative gene expression: quantitative validation by real time PCR and application to studies of alcoholic liver disease in primates.

The small quantities of tissue available for most studies of human disease are a significant limitation for meaningful gene expression profiling. The Atlas Switch Mechanism At the 5' end of Reverse Transcript (SMART) probe amplification kit uses as little as 50 ng of total RNA to generate complex cDNA probes for DNA array and other analyses. However, the extent to which this attractive methodology maintains representation of relative gene expression has not been quantified.

Effects of alcohol consumption on eight circulating markers of liver fibrosis.

A number of circulating breakdown products of collagen or other components of extracellular matrix, matrix degrading metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been proposed as markers of hepatic fibrosis. However, the published results lack consistency. Since many of the patients with fibrosis studied were alcoholics, the question was raised whether recent alcohol consumption may affect the results obtained.