Development Of Alcoholic Steatohepatitis Research Articles

P2X7 Receptor in Alcoholic Steatohepatitis and Alcoholic Liver Fibrosis.

Alcoholic liver disease is one of the most common chronic liver diseases in the world. It is a liver disease caused by prolonged heavy drinking and its main clinical features are nausea, vomiting, enlargement of the liver, and jaundice. Recent studies suggest that Kupffer cell-mediated inflammatory response is a core driver in the development of alcoholic steatohepatitis and alcoholic liver fibrosis. As a danger signal, extracellular ATP activates the assembly of NLPR3 inflammasome by acting on purine P2X7 receptor, the activated NLRP3 inflammasome prompts ASC to cleave pro-cCaspase-1 into active caspase-1in KCs. Active caspase-1 promotes the conversion of pro-IL-1β to IL-1β, which further enhances the inflammatory response. Here, we briefly review the role of the P2X7R-NLRP3 inflammasome axis in the pathogenesis of alcoholic liver disease and the evolution of alcoholic steatohepatitis and alcoholic liver fibrosis. Regulation of the inflammasome axis of P2X7R-NLRP3 may be a new approach for the treatment of alcoholic liver disease.

Small intestinal lamina propria immune cells dyshomeostasis is associated with alcoholic steatohepatitis in the mouse

Abstract The intestine represents the largest compartment of the immune system. Small intestinal lamina propria (SILP) immune processes are increasingly implicated in controlling disease development in the body. We have shown that reduction of tight junction proteins, system dysbiosis, and endotoxins translocation to the liver accounts for alcohol-induced steatohepatitis. However, the underlying mechanisms are still unclear. The present study investigated the effects of SILP antigen presenting cells dyshomeostasis on the pathogenesis of alcoholic steatohepatitis. Alcohol-induced liver inflammation was analyzed by inflammatory immune cells infiltration and proinflammatory cytokine gene expression. Chronic alcohol exposure (8 weeks) not only cause enteric dysbiosis but also increased plasma endotoxins (LPS) levels. The frequency of CD64-CD45+MHCII+CD11chi dendritic cells and CD64+F4/80+CD11b+ macrophage were both increased in SILP after chronic alcohol exposure. Further analysis demonstrated that alcohol exposure differently regulates CD103+ and CD103- dendritic cells subsets ratio. Intestinal IL-12p70 was significantly decreased after alcohol exposure. alcohol feeding also increased th2 cells but decreased th1 cells in SILP. The present study demonstrated that small intestinal immune cells activation may account for alcohol-induced dysbiosis, and thereby being a pathophysiological factor in the development of alcoholic steatohepatitis.

Hepatic Knockdown of Splicing Regulator Slu7 Ameliorates Inflammation and Attenuates Liver Injury in Ethanol-Fed Mice

Aberrant precursor mRNA splicing plays a pivotal role in liver diseases. However, roles of splicing regulators in alcoholic liver disease are unknown. Herein, we investigated a splicing regulator, Slu7, in the development of alcoholic steatohepatitis. Adenovirus-mediated alteration of hepatic Slu7 expression in mice pair fed either with or without (as control) ethanol in their diet was used. Knockdown of hepatic Slu7 by adenovirus-Slu7shRNA treatment ameliorated inflammation and attenuated liver injury in mice after ethanol administration. Mechanistically, reducing liver Slu7 expression increased the expression of sirtuin 1 (SIRT1) full-length and repressed the splicing of SIRT1 into SIRT1-ΔExon8 isoform in ethanol-fed mice. Knockdown of hepatic Slu7 in the ethanol-fed mice also ameliorated splicing of lipin-1 and serine/arginine-rich splicing factor 3 (Srsf3). In concordance with ameliorated splicing of SIRT1, lipin-1, and Srsf3, knockdown of hepatic Slu7 inhibited the activity of NF-κB, normalized iron and zinc homeostasis, reduced oxidative stress, and attenuated liver damage in ethanol-fed mice. In addition, hepatic Slu7 was significantly elevated in patients with alcoholic steatohepatitis. Our present study illustrates a novel role of Slu7 in alcoholic liver injury and suggests that dysregulated Slu7 may contribute to the pathogenesis of human alcoholic steatohepatitis.

MitoNEET Deficiency Alleviates Experimental Alcoholic Steatohepatitis in Mice by Stimulating Endocrine Adiponectin-Fgf15 Axis

MitoNEET (mNT) (CDGSH iron-sulfur domain-containing protein 1 or CISD1) is an outer mitochondrial membrane protein that donates 2Fe-2S clusters to apo-acceptor proteins. In the present study, using a global mNT knock-out (mNTKO) mouse model, we investigated the in vivo functional role of mNT in the development of alcoholic steatohepatitis. Experimental alcoholic steatohepatitis was achieved by pair feeding wild-type (WT) and mNTKO mice with Lieber-DeCarli ethanol-containing diets for 4 weeks. Strikingly, chronically ethanol-fed mNTKO mice were completely resistant to ethanol-induced steatohepatitis as revealed by dramatically reduced hepatic triglycerides, decreased hepatic cholesterol level, diminished liver inflammatory response, and normalized serum ALT levels. Mechanistic studies demonstrated that ethanol administration to mNTKO mice induced two pivotal endocrine hormones, namely, adipose-derived adiponectin and gut-derived fibroblast growth factor 15 (Fgf15). The elevation in circulating levels of adiponectin and Fgf15 led to normalized hepatic and serum levels of bile acids, limited hepatic accumulation of toxic bile, attenuated inflammation, and amelioration of liver injury in the ethanol-fed mNTKO mice. Other potential mechanisms such as reduced oxidative stress, activated Sirt1 signaling, and diminished NF-κB activity also contribute to hepatic improvement in the ethanol-fed mNTKO mice. In conclusion, the present study identified adiponectin and Fgf15 as pivotal adipose-gut-liver metabolic coordinators in mediating the protective action of mNT deficiency against development of alcoholic steatohepatitis in mice. Our findings may help to establish mNT as a novel therapeutic target and pharmacological inhibition of mNT may be beneficial for the prevention and treatment of human alcoholic steatohepatitis.

Hepatic-specific lipin-1 deficiency exacerbates experimental alcohol-induced steatohepatitis in mice

Lipin-1 regulates lipid metabolism by way of its function as an enzyme in the triglyceride synthesis pathway and as a transcriptional coregulatory protein and is highly up-regulated in alcoholic fatty liver disease. In the present study, using a liver-specific lipin-1-deficient (lipin-1LKO) mouse model, we aimed to investigate the functional role of lipin-1 in the development of alcoholic steatohepatitis and explore the underlying mechanisms. Alcoholic liver injury was achieved by pair feeding wild-type and lipin-1LKO mice with modified Lieber-DeCarli ethanol-containing low-fat diets for 4 weeks. Surprisingly, chronically ethanol-fed lipin-1LKO mice showed markedly greater hepatic triglyceride and cholesterol accumulation, and augmented elevation of serum liver enzymes accompanied by increased hepatic proinflammatory cytokine expression. Our studies further revealed that hepatic removal of lipin-1 in mice augmented ethanol-induced impairment of hepatic fatty acid oxidation and lipoprotein production, likely by way of deactivation of peroxisome proliferator-activated receptor γ coactivator-1 alpha, a prominent transcriptional regulator of lipid metabolism. Liver-specific lipin-1 deficiency in mice exacerbates the development and progression of experimental alcohol-induced steatohepatitis. Pharmacological or nutritional modulation of hepatic lipin-1 may be beneficial for the prevention or treatment of human alcoholic fatty liver disease.

The role of ethanol metabolism in development of alcoholic steatohepatitis in the rat

The importance of ethanol metabolism in the development of alcoholic liver disease remains controversial. The present study examined the effects of selective inhibition of the cytochrome P450 enzyme CYP2E1 compared with the inhibition of overall ethanol metabolism on the development of alcoholic steatohepatitis. Adult male Sprague–Dawley rats were fed via total enteral nutrition for 45 days with or without 10–12 g/kg/d ethanol. Some groups were given 200 mg/kg/d of the CYP2E1 inhibitor diallyl sulfide (DAS). Other groups were treated with 164 mg/kg/d of the alcohol dehydrogenase (ADH) inhibitor 4-methylpyrazole (4-MP) and dosed at 2–3 g/kg/d ethanol to maintain similar average urine ethanol concentrations. Liver pathology scores and levels of apoptosis were elevated by ethanol ( P < .05) but did not differ significantly on cotreatment with DAS or 4-MP. However, liver triglycerides were lower when ethanol-fed rats were treated with DAS or 4-MP ( P < .05). Serum alanine aminotransferase values were significantly lower in ethanol-fed 4-MP–treated rats indicating reduced necrosis. Hepatic oxidative stress and the endoplasmic reticulum (ER) stress marker tribbles-related protein 3 were increased after ethanol ( P < .05); further increased by DAS but partly attenuated by 4-MP. Both DAS and 4-MP reversed ethanol increases in the cytokine, tumor necrosis factor-alpha (TNF-α), and the chemokine CXCL-2 ( P < .05). However, neither inhibitors prevented ethanol suppression of interleukins IL-4 or IL-12. Moreover, neither inhibitors prevented ethanol increases in tumor growth factor-beta mRNA. Ethanol and DAS additively induced hepatic hyperplasia ( P < .05). These data suggest that a significant proportion of hepatic injury after ethanol exposure is independent of alcohol metabolism. Ethanol metabolism by CYP2E1 may be linked in part to triglyceride accumulation, to induction of TNF-α, and to chemokine production. Ethanol metabolism by ADH may be linked in part to oxidative and ER stress and necrotic injury.

HISTOPATHOLOGY OF ALCOHOLIC LIVER DISEASE

Alcohol abuse and diseases related to alcohol use, when considered together, constitute the third largest health problem in the United States and affect more than 10 million Americans. Twenty-five percent to 30% of hospitalizations are related to alcohol abuse, and 200,000 deaths each year are caused by alcohol-related disease.15, 75 As shown in Table 1, alcoholic cirrhosis has the highest mortality rates among all the different types of cirrhosis.60 The role of liver biopsy in the evaluation of alcohol-related liver disease has been questioned by some who believe the information obtained from a biopsy may not add significantly to that available from clinical laboratory data and radiology findings.2, 68 Liver biopsy is relatively safe, however, with an associated morbidity of 0.1% to 0.6% and a mortality rate of 0.01% to 0.03%.30, 32, 57 There is also relatively small interobserver variation in the histologic interpretation of alcoholic liver disease (ALD), with greater agreement in samples containing more than six portal tracts.8 Liver biopsies are not routinely performed in the diagnosis and treatment of ALD, so the true incidence of the various histologic changes associated with alcohol use is difficult to determine because the group of patients who are biopsied are not randomly selected. If we set aside objections to the nonrandom nature of the population sampled, however, some interesting facts emerge. Biopsies of the livers of several groups of alcohol abusers showed no pathologic changes in 15% of the livers sampled, 40% of the biopsies showed simple fatty changes, 15% showed alcoholic hepatitis (AH), 10% demonstrated cirrhosis, and 20% had changes not related to alcohol abuse.5 Recent studies demonstrate a strong association between allelic polymorphisms within the tumor necrosis factor ∝ promoter region and the development of alcoholic steatohepatitis and cirrhosis in heavy drinkers.10, 33 This article reviews the major histopathologic features of alcohol-related liver disease and emphasizes the important prognostic features. These morphologic features of ALD may exist independently of each other and do not necessarily represent a continuum of changes (Fig. 1).