Involvement and mechanism of DGAT2 upregulation in the pathogenesis of alcoholic fatty liver disease
ABSTRACT The mechanisms involved in the development of alcoholic liver disease (ALD) are not well established. We investigated the involvement of acyl-CoA: diacylglycerol acyltransferase 2 (DGAT2) upregulation in mediating hepatic fat accumulation induced by chronic alcohol consumption. Chronic alcohol feeding caused fatty liver and increased hepatic DGAT2 gene and protein expression, concomitant with a significant suppression of hepatic MAPK/ERK kinase/extracellular regulated kinase 1/2 (MEK/ERK1/2) activation. In vitro studies demonstrated that specific inhibitors of the MEK/ERK1/2 pathway increased DGAT2 gene expression and triglyceride (TG) contents in HepG2 cells, whereas epidermal growth factor, a strong ERK1/2 activator, had the opposite effect. Moreover, chronic alcohol feeding decreased hepatic S-adenosylmethionine (SAM): S-adenosylhomocysteine (SAH) ratio, an indicator of disrupted transmethylation reactions. Mechanistic investigations revealed that N-acetyl-S-farnesyl-L-cysteine, a potent inhibitor of isoprenylcysteine carboxyl methyltransferase, suppressed ERK1/2 activation, followed by an enhanced DGAT2 expression and an elevated TG content in HepG2 cells. Lastly, we demonstrated that the beneficial effects of betaine supplementation in ALD were associated with improved SAM/SAH ratio, alleviated ERK1/2 inhibition, and attenuated DGAT2 upregulation. In conclusion, our data suggest that upregulation of DGAT2 plays an important role in the pathogenesis of ALD, and that abnormal methionine metabolism contributes, at least partially, to DGAT2 upregulation via suppression of MEK/ERK1/2 activation.
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- "iet showed a remarkable suppression of hepatic ERK1 / 2 activation ( Wang et al . , 2010a ) . On the opposite side , an increase in the level of phosphorylated ERK1 / 2 improved liver steatosis ( Aghazadeh and Yazdanparast , 2010 ) . Chronic alcohol also caused a signif - icant suppression of hepatic ERK1 / 2 activation and triggered fatty liver ( Wang et al . , 2010b ) . We hypothesize that one of the MEK / ERK targets could be C / EBPa or C / EBPb . ERK can phosphorylate C / EBPa at Ser 21 ( Ross et al . , 2004 ) . Moreover , phosphorylation of C / EBPb at Thr235 by ERK2 is a key determinant of its capacity for transactivation ( Nakajima et al . , 1993 ) . Based on these studies , we suggest that p"
ABSTRACT: The small heterodimer partner (SHP, NR0B2) is an atypical nuclear receptor that lacks DNA-binding domain. It interacts with and inhibits many transcription factors, affecting key metabolic processes including bile acid, cholesterol, fatty acid and drug metabolism. Our aim was to determine the influence of steatotic drugs and non-alcoholic fatty liver disease (NAFLD) on SHP expression, and to investigate the potential mechanisms. SHP was found repressed by steatotic drugs (valproate, doxycycline, tetracycline and cyclosporin A) in cultured hepatic cells, and in the livers of different animal models of NAFLD: iatrogenic (tetracycline treated rats), genetic (glycine N-methyltransferase deficient mice) and nutritional (mice fed a methionine and choline deficient diet). Among the different transcription factors investigated, CCAAT-enhancer-binding protein α (C/EBPα) showed the strongest dominant-repressive effect on SHP expression in HepG2 and human hepatocytes. Reporter assays revealed that the inhibitory effect of C/EBPα and steatotic drugs co-localize between -340 and -509 bp of the SHP promoter and mutation of a predicted C/EBPα response element at -473 bp abolished SHP repression by both C/EBPα and drugs. Moreover, inhibition of major stress signaling pathways demonstrated that the mitogen-activated protein kinase kinase 1/2 pathway activates while the phosphatidylinositol 3 kinase pathway represses SHP in a C/EBP-dependent manner. We conclude that SHP is downregulated by several steatotic drugs and in advanced NAFLD. These conditions can activate signals that target C/EBPα and consequently repress SHP, thus favoring the progression and severity of NAFLD. The American Society for Pharmacology and Experimental Therapeutics.Molecular pharmacology 01/2015; 87(4). DOI:10.1124/mol.114.096313 · 4.13 Impact Factor
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- "Increased hepatic concentrations of SAM can activate cystathionine-synthase and lead to upregulation of the trans-sulfuration pathway, to increase synthesis of glutathione and attenuate oxidative stress. Thus, betaine can ameliorate ALD by attenuating fatty liver, inflammation, and fibrosis . "
ABSTRACT: Complementary and alternative medicine soughts and encompasses a wide range of approaches; its use begun in ancient China at the time of Xia dynasty and in India during the Vedic period, but thanks to its long-lasting curative effect, easy availability, natural way of healing, and poor side-effects it is gaining importance throughout the world in clinical practice. We conducted a review describing the effects and the limits of using herbal products in chronic liver disease, focusing our attention on those most known, such as quercetin or curcumin. We tried to describe their pharmacokinetics, biological properties, and their beneficial effects (as antioxidant role) in metabolic, alcoholic, and viral hepatitis (considering that oxidative stress is the common pathway of chronic liver diseases of different etiology). The main limit of applicability of CAM comes from the lacking of randomized, placebo-controlled clinical trials giving a real proof of efficacy of those products, so that anecdotal success and personal experience are frequently the driving force for acceptance of CAM in the population.Evidence-based Complementary and Alternative Medicine 09/2012; 2012(9):837939. DOI:10.1155/2012/837939 · 1.88 Impact Factor
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ABSTRACT: While it is clear that a single hematopoietic stem cell (HSC) is capable of giving rise to all other hematopoietic cell types, the differentiation paths beyond HSC remain controversial. Contradictory reports on the lineage potential of progenitor populations have questioned their physiological contribution of progenitor populations to multilineage differentiation. Here, we established a lineage tracing mouse model that enabled direct assessment of differentiation pathways in vivo. We provide definitive evidence that differentiation into all hematopoietic lineages, including megakaryocyte/erythroid cell types, involves Flk2-expressing non-self-renewing progenitors. A Flk2+ stage was used during steady-state hematopoiesis, after irradiation-induced stress and upon HSC transplantation. In contrast, HSC origin and maintenance do not include a Flk2+ stage. These data demonstrate that HSC specification and maintenance are Flk2 independent, and that hematopoietic lineage separation occurs downstream of Flk2 upregulation.Cell stem cell 07/2011; 9(1):64-73. DOI:10.1016/j.stem.2011.04.021 · 22.27 Impact Factor