Palash Mandal

Effect of alcohol on adipose tissue: a review on ethanol mediated adipose tissue injury

Background: Alcohol consumption has been in existence in the world for many centuries and it is the major cause of death and injury worldwide. Alcoholic liver disease (ALD) is caused due to excess and chronic alcohol intake. Studies across the globe have identified several pathways leading to ALD. Adipose tissue which has been considered as an energy storage organ is also found to play a major role in ALD progression by secreting hormones and cytokines known as adipokines or adipocytokines. Ethanol affects the metabolic and innate immune activities of adipose tissue contributing to alcohol-induced injury of the tissues. Objective: We aimed at 1) summarizing the metabolism and progression of ALD 2) summarizing about the structure and effect of ethanol induced oxidative stress on adipose tissue 3) reviewing the available data on the effect of ethanol on adipose tissue mass and adipokine secretion in both rodent models and alcoholic patients. Methods: The article is summarized based on the original literature and reviews in studying the effect of ethanol on adipose tissue. Results: Studies on alcoholic patients and rodent models has shown that chronic ethanol consumption reduces adipose tissue mass and causes CYP2E1 mediated oxidative stress and inflammation of adipose tissue. Further hyperlipolysis is observed in adipose tissue that leads to excess fatty acid release that gets transported and deposited in the liver resulting in hepatic steatosis. Conclusion: Studies show that adipose tissue plays a major role in the progression of ALD. So understanding of the mechanisms linking ethanol induced adipose tissue injury with ALD progression would help us in identifying potential therapeutic targets.

Evaluating the effect of diallyl sulfide on regulation of inflammatory mRNA expression in 3T3L1 adipocytes and RAW 264.7 macrophages during ethanol treatment

Abstract Diallyl sulfide (DAS) has been studied extensively for its alleged role as an anticancer and protective agent. Alcohol influences and effects on human health have been extensively studied. However, investigations toward developing and testing therapeutic agents that can reduce the tissue injury caused by ethanol are scarce. In this backdrop, this study was designed to explore the potential effect of DAS in reducing alcohol induced damage of 3T3L1 adipocytes and RAW 264.7 macrophages. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay was performed to determine the DAS effect on cell viability. Reactive oxygen species (ROS) production was assessed by flow cytometer. Expression of inflammatory genes was studied by the qRT-PCR method. Our study results showed that DAS at concentrations less than 200 μM was not toxic to the cells and the viability of ethanol-exposed 3T3L1 adipocyte cells was found to be significantly increased when ethanol-exposed cells were treated with DAS. Further, treatment of ethanol-exposed 3T3L1 cells with 100 μM DAS for 24 h was found to reduce ethanol induced ROS production, expression of pro-inflammatory cytokines, and enhance anti-inflammatory cytokine production in the cells. Also, 100 μM DAS was found to increase the expression of M2 phenotype-specific genes in ethanol-exposed RAW 264.7 macrophage cells. Further, 100 μM DAS also improved the levels of lipid accumulation in 3T3L1 adipocytes that was down-regulated by ethanol exposure. Taken together, our study results imply that DAS may be effective in reducing ethanol induced injury of cells thereby suggesting its potential to be used in drug formulations.

Association of Advanced Glycation End Products (AGEs) with Diabetic Nephropathy and Alcohol Consumption

The occurrence of diabetes is accelerating worldwide, with consequent increase in the secondary complication like diabetic nephropathy (DN). Diabetic nephropathy refers to a set of structural and functional abnormalities of kidney in patients with diabetes. Detrimental changes like glomerular hypertrophy, glomerulosclerosis, hyperfiltration, proteinuria, etc. occur in DN. One of the major pathways suggested for the pathogenesis is formation of Advanced Glycation End Products (AGEs) via non enzymatic glycation (NEG). NEG is the process in which reducing sugars irreversibly modify free amino groups of proteins, by various events leading to the formation of a Schiff base resulting in Amadori products, culminating into AGEs. AGEs activate several cascades of intracellular signaling via interaction with Receptor for AGEs (RAGE) that results in responses like release of pro-inflammatory cytokines resulting in inflammation, autophagy and programmed cell death. AGEs can also come into circulation from baked food and processed food items. AGEs can also be formed through various oxidative reactions, including the chronic use of alcohol. Alcohol in excess could result in accumulation of acetaldehyde that would lead to insulin resistance. Many risk factors like race, genetic susceptibility, hypertension, hyperglycemia, hyper filtration, smoking, advanced age, male sex, and high-protein diet account for development of DN. Therapeutic interventions include glycemic control, control of blood pressure. This review focuses on the formation of AGEs via non enzymatic glycation, its implications in pathogenesis of DN and therapies designed to break AGEs so as to prevent the development of DN.

Potential Molecular Mechanism of Probiotics in Alcoholic Liver Disease

Alcohol consumption and its abuse are significant prevalent cause for liver diseases and death worldwide. Increased bacterial endotoxin in the portal circulation, the plasma ratio of liver enzymes like alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride implies the symbiotic relation between the gut and liver plays a key function in alcoholic liver disease (ALD). Consumption of alcohol leads to gut dysbiosis and informalities of the intestinal barrier, hyper gut permeability, oxidative stress, inflammation and adversely affect adipose tissue metabolism, and those are mainly recognized as major factors for progression of alcoholic liver disease. Alteration of gut microbiota is referred to as bacterial overgrowth which leads to the release of bacterial products to change in commercial/pathogenic microbiota equilibrium. Lipopolysaccharide (LPS) derived inflammatory signal renders inflammation in alcoholic liver disease. Increase in concentration of lipopolysaccharide leads to activation of toll-like receptor 4 (TLR4) and alteration in micro RNA (miRNA) expression at the transcription level. Activation of myeloid differentiation factor 88 (MyD88) pathways eventually produces pro inflammatory cytokine activation that is an important mediator of alcoholic liver disease. However, there is no effectual Food and Drug Administration (FDA) approved treatment for any stage of alcoholic liver disease. Thus, the potential therapeutic approach for alcoholic liver disease is restoration and alteration of gut microbiota. With the increasing importance of gut microbiota in the onset and occurrence of a variety of diseases, the potential use of probiotics in ALD is receiving more exploration and clinical attention. Probiotic administration is nontoxic, inexpensive and noninvasive strategy with minimal side effects compared to antibiotic therapy and surgery. Yet, there is no substantial evidence on the efficient molecular mechanism regarding mode of action of probiotics on ALD as therapeutics. This review summarizes the research done on gut liver-axis and potential mechanism of probiotic in alcoholic liver disease.

Chapter 10 - Stellate Cells in Alcoholic Hepatitis

Chronic alcohol consumption is a major cause of death worldwide. Chronic, heavy alcohol consumption leads to alcoholic liver disease (ALD), which progresses from steatosis to steatohepatitis, with the eventual development of fibrosis and cirrhosis in many heavy drinkers. Recent evidence indicates that multiple stages of ALD, including fibrosis, are reversible, thus understanding the underlying molecular mechanisms involved in the progression of ALD is critical. Hepatic stellate cells (HSCs) play a major role in the progression of ALD to fibrosis. Metabolism of alcohol in the liver results in the activation and proliferation of HSCs mediated, at least in part, by factors released from both hepatocytes and Kupffer cells, the resident liver macrophages. Here we review our current understanding of the specific pathways by which alcohol and alcohol metabolism contribute to the activation of HSC and the progression of fibrosis.