MicroRNA-483-5p Inhibits Hepatocellular Carcinoma Cell Proliferation, Cell Steatosis, and Fibrosis by Targeting PPARα and TIMP2.

MicroRNAs (miRNAs) are small non-coding RNA molecules that bind with the 3' untranslated regions (UTRs) of genes to regulate expression. Downregulation of miR-483-5p (miR-483) is associated with the progression of hepatocellular carcinoma (HCC). However, the significant roles of miR-483 in nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver diseases (AFLD), and HCC remain elusive.

Pathogenesis of alcoholic liver disease: the role of nuclear receptors.

Ethanol consumption causes fatty liver, which can lead to inflammation, fibrosis, cirrhosis and even liver cancer. The molecular mechanisms by which ethanol exerts its damaging effects are extensively studied, but not fully understood. It is now evident that nuclear receptors (NRs), including retinoid x receptor alpha and peroxisome proliferator-activated receptors, play key roles in the regulation of lipid homeostasis and inflammation during the pathogenesis of alcoholic liver disease (ALD).

Mechanisms of resistance of hepatocyte retinoid X receptor alpha-null mice to WY-14,643-induced hepatocyte proliferation and cholestasis.

Peroxisome proliferators, such as the lipid-lowering fibrates that function as agonists for peroxisome proliferator-activated receptor alpha (PPARalpha), induce liver tumors in rodents and may produce cholestasis in humans. Considerable attention has focused on peroxisome proliferator-induced hepatocellular carcinoma, a phenomenon not noted in man, whereas limited studies examine fibrates and other therapeutic drugs that induce cholestasis, a common finding in humans. Moreover, the mechanisms by which fibrates induce hepatocyte proliferation and cholestasis are still not fully understood.

Hepatic effects of a methionine-choline-deficient diet in hepatocyte RXRalpha-null mice.

Retinoid X receptor-alpha (RXRalpha) is an obligate partner for several nuclear hormone receptors that regulate important physiological processes in the liver. In this study the impact of hepatocyte RXRalpha deficiency on methionine and choline deficient (MCD) diet-induced steatosis, oxidative stress, inflammation, and hepatic transporters gene expression were examined. The mRNA of sterol regulatory element-binding protein (SREBP)-regulated genes, important for lipid synthesis, were not altered in wild type (WT) mice, but were increased 2.

The pathogenesis of ethanol versus methionine and choline deficient diet-induced liver injury.

The differences and similarities of the pathogenesis of alcoholic (ASH) and non-alcoholic steatohepatitis (NASH) were examined. Mice (six/group) received one of four Lieber-Decarli liquid diets for 6 weeks: (1) paired-fed control diet; (2) control diet with ethanol (ethanol); (3) paired-fed methionine/choline deficient (MCD) diet; and (4) MCD plus ethanol (combination). Hepatotoxicity, histology, and gene expression changes were examined.

Hepatocyte retinoid X receptor alpha-dependent regulation of lipid homeostasis and inflammatory cytokine expression contributes to alcohol-induced liver injury.

Hepatocyte retinoid X receptor alpha (RXRalpha)-deficient mice are more sensitive to ethanol toxicity than wild-type mice. Because RXRalpha-mediated pathways are implicated in lipid homeostasis and the inflammatory response, we hypothesized that a compromise in lipid metabolism and associated production of proinflammatory mediators are responsible for the hepatotoxicity observed in ethanol-treated hepatocyte RXRalpha-deficient mice. Wild-type and hepatocyte RXRalpha-deficient mice were fed ethanol-containing diets or pair-fed control diets for 6 weeks.

The role of retinoid X receptor alpha in regulating alcohol metabolism.

There is substantial overlap in retinol and alcohol metabolism. Mice that lack retinoic acid (RA) receptor retinoid X receptor alpha (RXRalpha) expression in the liver are more susceptible to alcoholic liver disease. To investigate the interaction between RXRalpha and alcoholic liver disease, ethanol metabolism was studied in hepatocyte RXRalpha-deficient [RXRalpha knockout (KO)] mice.

The effect of ethanol, ethanol metabolizing enzyme inhibitors, and Vitamin E on regulating glutathione, glutathione S-transferase, and S-adenosylmethionine in mouse primary hepatocyte.

We studied changes in the antioxidant systems involved in hepatoprotection after ethanol exposure in primary culture of mouse hepatocytes. Ethanol decreased glutathione (GSH) levels and the S-adenosylmethionine (SAMe) to S-adenosylhomocysteine (SAH) ratio by 53% and 22%, respectively. Cytosolic glutathione S-transferase (GST) activity was significantly lower in ethanol exposed hepatocytes, which was accompanied by an increase in GST activity in the culture medium.

High prevalence of cytochrome P450 2A6*1A alleles in a black African population of Ghana.

Objective: We investigated the frequencies of the functionally important variants of the CYP2A6 gene in black African populations.

Methods: Using genomic DNA sequencing, polymerase chain reaction (PCR)-restriction fragment length polymorphism and allele-specific PCR, the allele frequencies of CYP2A6 *1A, *1B, *2, *4A, *5, *6, *7, *8, *9, *10 and * 11 among 120 black Africans- including 105 Ghanaians, 12 Nigerians, 2 Ivorians and 1 Ugandan-were determined.

Results: The allele frequencies were 80.

Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male Japanese smokers.

We reported previously that subjects homozygous for the cytochrome P450 2A6 (CYP2A6) (*)4 have a lower risk of lung cancer. The purpose of this study was to clarify whether or not the alterations of smoking behavior and risk for lung cancer could be found in subjects possessing novel CYP2A6 variants discovered recently. An epidemiological study was performed with 1094 cases and 611 controls in male Japanese smokers.

Inhibition of glutathione S-transferases by thonningianin A, isolated from the African medicinal herb, Thonningia sanguinea, in vitro.

There is evidence that increased expression of glutathione S-transferase (EC: 2.5.1.

Selective suppression of cytochrome P450 gene expression by the medicinal herb, Thonningia sanguinea in rat liver.

The effect of the administration of Thonningia sanguinea (T. S.) on the abundance of individual components of the cytochrome P450 monooxygenase enzyme was examined using Western blotting and competitive reverse-transcriptase-polymerase chain reaction (RT-PCR).

Antioxidant properties of Thonningianin A, isolated from the African medicinal herb, Thonningia sanguinea.

The antioxidant properties of Thonningianin A (Th A), an ellagitannin, isolated from the methanolic extract of the African medicinal herb, Thonningia sanguinea were studied using the NADPH and Fe2+/ascorbate-induced lipid peroxidation (LPO), electron spin resonance spectrometer and the deoxyribose assay. Th A at 10 microM inhibited both the NADPH and Fe2+/ascorbate-induced LPO in rat liver microsomes by 60% without inhibitory effects on cytochrome P450 activity. Th A was similar to the synthetic antioxidant, tannic acid, as an inhibitor of both the NADPH and Fe2+/ascorbate-induced LPO but potent than gallic acid, vitamin C and vitamin E.