Insulin Resistance, Ceramide Accumulation, and Endoplasmic Reticulum Stress in Human Chronic Alcohol-Related Liver Disease

Division of Gastroenterology, Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
Oxidative Medicine and Cellular Longevity (Impact Factor: 3.36). 04/2012; 2012(10):479348. DOI: 10.1155/2012/479348
Source: PubMed


Chronic alcohol-related liver disease (ALD) is mediated by insulin resistance, mitochondrial dysfunction, inflammation, oxidative stress, and DNA damage. Recent studies suggest that dysregulated lipid metabolism with accumulation of ceramides, together with ER stress potentiate hepatic insulin resistance and may cause steatohepatitis to progress.
We examined the degree to which hepatic insulin resistance in advanced human ALD is correlated with ER stress, dysregulated lipid metabolism, and ceramide accumulation.
We assessed the integrity of insulin signaling through the Akt pathway and measured proceramide and ER stress gene expression, ER stress signaling proteins, and ceramide profiles in liver tissue.
Chronic ALD was associated with increased expression of insulin, IGF-1, and IGF-2 receptors, impaired signaling through IGF-1R and IRS1, increased expression of multiple proceramide and ER stress genes and proteins, and higher levels of the C14, C16, C18, and C20 ceramide species relative to control.
In human chronic ALD, persistent hepatic insulin resistance is associated with dysregulated lipid metabolism, ceramide accumulation, and striking upregulation of multiple ER stress signaling molecules. Given the role of ceramides as mediators of ER stress and insulin resistance, treatment with ceramide enzyme inhibitors may help reverse or halt progression of chronic ALD.

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    • "First of all, acetaldehyde is a robust ER stress inducer [68]. Additionally, because studies of ceramiderelated ER stress are currently in progress [65] [69], the contribution of excessive FA-induced ER stress to ALD remains obscure. However, past experimental evidence has provided sufficient insight into ER stress caused in the hepatocytes of ALD by excess FA [61-63]. "
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    ABSTRACT: Steatosis is a characteristic morphological change of alcoholic liver disease, but its pathologic significance is still obscure. Regardless of cell types, intracellular lipid droplets are coated with a phospholipid monolayer, on which many kinds of lipid droplet-associated proteins are present. These proteins, such as the perilipin family of proteins and the cell death inducing DNA fragmentation factor (DFF) 45-like effectors, are recognized to play important roles in lipid metabolism in the physiological settings. In addition, recent lipidology studies have revealed that expression of the lipid droplet-associated proteins possibly participate in the pathologic processes of many metabolic disorders, including fatty liver and insulin resistance. Hence, controlling protein expressions is expected to offer novel therapeutic options. In this review, we summarize collected data concerning the potential contribution of the lipid droplet-associated proteins to the development of alcoholic fatty liver. Without exception, existing data indicates that the lipid droplet-associated proteins, especially the perilipin family proteins, are important factors in alcoholic fatty liver. These proteins exert a prosteatotic effect, and their expression is closely associated with lipotox-icity based on endoplasmic reticulum stress and oxidative injury. Although suppression of their expression may be beneficial, careful consideration is required because these proteins simultaneously function as protective factors against lipotoxicity.
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    • "In this regard, ALD and other forms of steatohepatitis are marked by altered lipid profiles, including those corresponding sphingolipids, particularly ceramides [14] [16] [19] [20] [21], and membrane phospholipids [22] [23] [24]. Since histopathological and imaging studies cannot distinguish underlying causes of steatohepatitis, additional diagnostic approaches are needed that could eventually lead to the development of molecularly targeted therapy. "

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    • "3.3. Effects of ethanol, NDEA, and both exposures on cerebellar neuronal and glial cell protein expression Cerebellar protein homogenates were used to measure Hu (neuronal), myelin-associated glycoprotein 1 (MAG-1; oligodendrocyte), glial fibrillary acidic protein (GFAP; astrocyte), Tau (neuronal cytoskeleton), phospho- Tau (pTau), choline acetyltransferase (ChAT), acetylcholinesterase (AChE), and 4-hydroxy-2-nonenal (HNE; lipid peroxidation adduct) protein expression by duplex ELISAs with results normalized to RPLPO [15]. Two-way ANOVA tests demonstrated no significant effects of ethanol, NDEA, or combined exposures on the expression levels of Hu, Tau, pTau, ChAT, or AChE, or relative levels of Tau phosphorylation (pTau/Tau) (Table 1). "

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