Fatty acids inhibit LAMP2-mediated autophagy flux via activating ER stress pathway in alcohol-related liver disease

Alcohol-related liver disease (ALD) is characterized by accumulation of hepatic free fatty acids (FFAs) and liver injury. The present study aimed to investigate if mechanistic target of rapamycin complex 1 (mTORC1) plays a role in FFA-induced organelle dysfunction, thereby contributing to the development of ALD. Cell studies were conducted to define the causal role and underlying mechanism of FFA-activated mTORC1 signaling in hepatocellular cell injury. C57BL/6J wild-type mice were subjected to chronic alcohol feeding with or without rapamycin to inhibit mTORC1 activation. We revealed that palmitic acid (PA)-induced ER stress and suppression of LAMP2 and autophagy flux were mTORC1-dependent as rapamycin reversed such deleterious effects. C/EBP homologous protein (CHOP) was downstream of ATF4 which partially modulated LAMP2. Supplementation with rapamycin to alcohol-fed mice attenuated mTORC1 activation and ER stress, restored LAMP2 protein, and improved autophagy, leading to amelioration of alcohol-induced liver injury. Induction of mTORC1 signaling and CHOP were also detected in the liver of patients with severe alcoholic hepatitis. This study demonstrates that hepatic FFAs play a crucial role in the pathogenesis of ALD by activating mTORC1 signaling, thereby inducing ER stress and suppressing LAMP2-autophagy flux pathway, which represents an important mechanism of FFA-induced hepatocellular injury.

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Role of the mTOR-autophagy-ER stress pathway in high fructose-induced metabolic-associated fatty liver disease

Acta Pharmacologica Sinica ◽

10.1038/s41401-021-00629-0 ◽

2021 ◽

Author(s):

Ya-lin Wang ◽

Xiu Zhou ◽

Dong-li Li ◽

Ji-ming Ye

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Er Stress ◽

Fatty Liver Disease ◽

High Fructose ◽

Stress Pathway

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2012/479348 ◽

2012 ◽

Vol 2012 ◽

pp. 1-17 ◽

Cited By ~ 56

Author(s):

Lisa Longato ◽

Kelsey Ripp ◽

Mashiko Setshedi ◽

Miroslav Dostalek ◽

Fatemeh Akhlaghi ◽

...

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Liver Disease ◽

Er Stress ◽

Enzyme Inhibitors ◽

Hepatic Insulin Resistance ◽

Stress Signaling ◽

Chronic Alcohol ◽

Related Liver Disease ◽

Ceramide Accumulation

Background. 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.Objective. We examined the degree to which hepatic insulin resistance in advanced human ALD is correlated with ER stress, dysregulated lipid metabolism, and ceramide accumulation.Methods. 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.Results. 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.Conclusions. 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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Differential regulation of the endoplasmic reticulum stress response in pancreatic β-cells exposed to long-chain saturated and monounsaturated fatty acids

Journal of Endocrinology ◽

10.1677/joe-08-0041 ◽

2008 ◽

Vol 197 (3) ◽

pp. 553-563 ◽

Cited By ~ 78

Author(s):

Eleftheria Diakogiannaki ◽

Hannah J Welters ◽

Noel G Morgan

Keyword(s):

Fatty Acids ◽

Endoplasmic Reticulum ◽

Stress Response ◽

Er Stress ◽

Initiation Factor ◽

Β Cells ◽

Pancreatic Β Cells ◽

Er Stress Response ◽

Stress Pathway ◽

Long Chain

Exposure of pancreatic β-cells to long-chain fatty acids leads to the activation of some components of the endoplasmic reticulum (ER) stress pathway and this mechanism may underlie the ability of certain fatty acids to promote β-cell death. We have studied ER stress in BRIN-BD11 β-cells exposed to either the saturated fatty acid palmitate (C16:0) or the monounsaturated palmitoleate (C16:1). Palmitate (0.025–0.25 mM) induced the expression of various markers of the RNA-dependent protein kinase-like ER eukaryotic initiation factor 2α (eIF2α) kinase (PERK)-dependent pathway of ER stress (phospho-eIF2α; ATF4, activating transcription factor 4 and C/EBP homologous protein (CHOP-10)) although it failed to promote the expression of the ER chaperone GRP78. By contrast, palmitoleate did not induce any markers of the ER stress pathway even at concentrations as high as 1 mM. When palmitate and palmitoleate were added in combination, a marked attenuation of the ER stress response occurred. Under these conditions, the levels of phospho-eIF2α, ATF4 and CHOP-10 were reduced to less than those found in control cells. Palmitoleate also attenuated the ER stress response to the protein glycosylation inhibitor, tunicamycin, and improved the viability of the cells exposed to this agent. Exposure of the BRIN-BD11 cells to the protein phosphatase inhibitor, salubrinal, in the absence of fatty acids resulted in increased eIF2α phosphorylation but this was abolished by co-incubation with palmitoleate. We conclude that saturated fatty acids activate components of the PERK-dependent ER stress pathway in β-cells, ultimately leading to increased apoptosis. This effect is antagonised by monounsaturates that may exert their anti-apoptotic actions by regulating the activity of one or more kinase enzymes involved in mediating the phosphorylation of eIF2α.

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