VLDL and apolipoprotein CIII induce ER stress and inflammation and attenuate insulin signalling via Toll-like receptor 2 in mouse skeletal muscle cells

Botteri, Gaia; Montori, Marta; Gumà, Anna; Pizarro, Javier; Cedó, Lídia; Escolà‐Gil, Joan Carles; Li, Diana; Barroso, Emma; Palomer, Xavier; Kohan, Alison B.; Vázquez‐Carrera, Manuel

doi:10.1007/s00125-017-4401-5

Cited by 32 publications

(20 citation statements)

References 50 publications

(65 reference statements)

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“…67 Additionally, incubation of myotubes with a neutralizing antibody against Toll-like receptor 2 (TLR2) abolished the effects of ApoCIII on ER stress, inflammation, and insulin resistance, indicating that the effects of ApoCIII are mediated by this receptor. 64 In summary, the ApoCIII-induced ER stress in skeletal muscles enhances expression of inflammatory mediators, and thus attenuates insulin signalling pathway. Moreover, the increase of hepatic lipid accumulation in the context of elevated plasma ApoCIII levels can lead to NAFLD, hepatic insulin resistance, and thus DM.…”

Section: Apociii-induced Insulin Resistancementioning

confidence: 99%

“…Moreover, ER stress inhibits insulin signalling by inducing serine phosphorylation of insulin receptor substrate 1 (IRS‐1) and it also down‐regulates the insulin receptor levels in adipocytes . Additionally, incubation of myotubes with a neutralizing antibody against Toll‐like receptor 2 (TLR2) abolished the effects of ApoCIII on ER stress, inflammation, and insulin resistance, indicating that the effects of ApoCIII are mediated by this receptor …”

Section: Mechanisms Linking Apociii and Dmmentioning

confidence: 99%

“…64 The ApoCIII-induced ER stress leads to activation of nuclear factor κB (NF-κΒ), which enhances the expression of inflammatory mediators, such as tumour necrosis factor alpha (TNF-a), interleukin 6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1). 64,65 Moreover, ER stress inhibits insulin signalling by inducing serine phosphorylation of insulin receptor substrate 1 (IRS-1) 66 and it also down-regulates the insulin receptor levels in adipocytes. 67 Additionally, incubation of myotubes with a neutralizing antibody against Toll-like receptor 2 (TLR2) abolished the effects of ApoCIII on ER stress, inflammation, and insulin resistance, indicating that the effects of ApoCIII are mediated by this receptor.…”

Section: Apociii-induced Insulin Resistancementioning

confidence: 99%

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Apolipoprotein CIII and diabetes. Is there a link?

Christopoulou

Tsimihodimos

Filippatos

et al. 2019

Diabetes Metabolism Res

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Summary Apolipoprotein CIII (ApoCIII), a small protein that resides on the surface of lipoprotein particles, is a key regulator of triglyceride metabolism. The inhibition of lipoprotein lipase (LPL), the increased assembly and secretion of very low‐density lipoproteins (VLDL) and the decreased reuptake of triglyceride‐rich lipoproteins (TRLs) by the liver are mechanisms associating elevated serum ApoCIII levels and hypertriglyceridemia. ApoCIII concentration is high in individuals with diabetes mellitus, indicating a possible positive correlation with impairment of glucose metabolism. The aim of this review (based on a Pubmed search until August 2018) is to present the possible mechanisms linking ApoCIII and deterioration of carbohydrate homeostasis. ApoCIII enhances pancreatic β‐cells apoptosis via an increase of the cytoplasmic Ca2+ levels in the insulin‐producing cells. In addition, overexpression of ApoCIII enhances non‐alcoholic fatty liver disease and exacerbates inflammatory pathways in skeletal muscles, affecting insulin signalling and thereby inducing insulin resistance. Moreover, recent studies reveal a possible mechanism of body weight increase and glucose production through a potential ApoCIII‐induced LPL inhibition in the hypothalamus. Also, the presence of ApoCIII on the surface of high‐density lipoprotein particles is associated with impairment of their antiglycemic and atheroprotective properties. Modulating ApoCIII may be a potent therapeutic approach to manage hypertriglyceridemia and improve carbohydrate metabolism.

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Section: Apociii-induced Insulin Resistancementioning

confidence: 99%

Section: Mechanisms Linking Apociii and Dmmentioning

confidence: 99%

Section: Apociii-induced Insulin Resistancementioning

confidence: 99%

See 1 more Smart Citation

Apolipoprotein CIII and diabetes. Is there a link?

Christopoulou

Tsimihodimos

Filippatos

et al. 2019

Diabetes Metabolism Res

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“…VLDL exposure in muscle also resulted in an increase mRNA of IL-6, CMP1 and TNF-α, as well as IRS Ser 307 phosphorylation, and reduced IkBα [33], these data indicate that disruption of fatty acid handling in skeletal muscle can induce ER stress, insulin resistance and inflammation.…”

Section: Er Stress and Unfolded Protein Responsementioning

confidence: 56%

Endoplasmic Reticulum Stress of Skeletal Muscle and Exercise Training Effects in Aging and Obesity

2018

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IntroductionThe increase in body fat and decrease in muscle mass during aging are associated with physical deterioration and degenerative diseases and cause obesity via the accumulation of abdominal fat. This increases insulin resistance as well as the production of cytokines (tumor necrosis factor-α, TNF-α; interleukin-4, IL-4; monocyte chemoattractant protein-1, MCP-1), which cause inflammation, and adipocytokines, which promote catabolism in muscles, thereby reducing muscle/ myo-function. These processes lead to obesity and ultimately to insulin resistance syndrome, diabetes, and cardiovascular diseases. Considering the recent domestic trend characterized by a rapidly aging population owing to an extension in the average life span and change in the population composition, it is necessary to analyze sarcopenic obesity and insulin resistance and to develop strategies for active prevention.In this review, the effects of aerobic exercise training, one of the major preventative methods for obesity, on endoplasmic reticulum (ER) stress and sarcopenic obesity caused by obesity and aging as well as insulin resistance syndrome were determined to analyze the correlations between these phenotypes. Asian J Kinesiol 2018; 20(3):1-10· DOI: https://doi.org/10.15758/ajk.2018.20.3 Endoplasmic reticulum (ER) stress associated with sarcopenic obesity in obesity and aging, which is a key factor in insulin resistance, are highly related. Long-term exercise training reduces ER stress via the activation of JUN N-terminal kinase (JNK) and reduction of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) decomposition and improves insulin resistance. Sarcopenia is associated with multiple factors, including increased pro-inflammation cytokine, oxidative stress, ER stress and fat infiltration as well as reduced mitochondrial function. Interaction between unfold protein response (UPR) and autophagy may play an important role to maintain the muscle protein quality control. The key factor in protein synthesis pathway for protein quality control is mammalian target of rapamycin complex 1 (mTORC1), indeed aging impairs contraction-induced human skeletal muscle mTORC1 signaling and protein synthesis. During exercise, mTOR pathway might be decreased that may result in an increase autophagy, because mTOR is a negative feedback factor for autophagy. Particularly, increased mTOR after exercise will be decrease autophagy. However, the effects of specific exercise training programs (type, intensity, time, frequency, etc.) and the mechanisms underlying these relationships are unclear. Therefore, it is necessary to establish the mechanisms of diabetes mellitus, focusing on sarcopenic obesity in obesity and aging, ER stress, and insulin resistance, and to analyze the effects of exercise training from a molecular biological perspective. ABSTRACT

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“…The non-alcoholic fatty liver disease (NAFLD) begins with hepatic steatosis, which is defined as the accumulation of triglycerides (TG) at the level of the cytoplasm, in histology is evidenced by the presence of droplets in cytoplasm of TG in more than 5% of the hepatocytes, steatosis may progress to a state of inflammation and cellular damage that may end in NAFLD and hepatic cirrhosis (6). In the pathogenesis of NAFLD it has been shown that the increase of free fatty acids leads to a deregulation of the ways of assimilation and release of free fatty acid in the liver, thus modifying the regulation of transcription of the genes of lipogenesis and their transport out of the liver (7,8). The excess of TG overloads the carrier VLDL molecules, so VLDL-TG of greater diameter that exceed the sinusoidal pores of epithelium accumulate in the liver, and may generate stress in the endoplasmic reticulum (ER) and the activation of the pathway NF-κB, which increase the transcription of genes encoding for pro-inflammatory cytokines (8,9).…”

Section: Introductionmentioning

confidence: 99%

Denitrase activity of Debaryomyces�hansenii reduces the oxidized compound 3‑nitrotyrosine in mice liver with colitis

et al. 2019

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The oxidation of tyrosine to 3-nitrotyrosine is irreversible, and due to this characteristic, 3-nitrotyrosine is used as a marker for oxidative stress in a range of diverse chronic and degenerative diseases. It has been established that the yeast Debaryomyces hansenii (D. hansenii) can assimilate free 3-nitrotyrosine as unique source of nitrogen, and during saline stress, has a high denitrase activity to detoxify this compound in a reaction that involves the liberation of nitrogen dioxide from 3-nitrotyrosine. However, until now it has not been determined whether D. hansenii can detoxify protein-bound 3-nitrotyrosine such as nitrated proteins present in different chronic illnesses. TThe aim of the present study was to evaluate the denitrase activity of D. hansenii to reduce 3-nitrotyrosine from liver proteins of mice with colitis. Firstly, the levels of reactive oxygen species of liver tissue of colitic and control mice were measured by the reaction with the 2'7'-dichlorofluorescein diacetate. Denitrase activity of D. hansenii was evaluated by incubating cell extracts of the yeast with protein extracts from livers of mice with colitis. Following incubation, 3-nitrotyrosine was measured, and to corroborate that denitrase reaction had occurred, the production of nitrites was measured. In samples of liver tissue from mice with colitis, the maximum levels of reactive oxygen species were up to two times higher compared with the control livers. Following the incubation of colitic liver samples with cell extracts of D. hansenii, it was observed that 3-nitrotyrosine decreased to the basal concentration of control liver samples, and that the concentration of nitrites was increased. These results indicate that denitrase of D. hansenii extracts can effectively detoxify 3-nitrotyrosine bound to proteins and that the extracts could be used to decrease protein oxidation damage in chronic degenerative diseases.

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VLDL and apolipoprotein CIII induce ER stress and inflammation and attenuate insulin signalling via Toll-like receptor 2 in mouse skeletal muscle cells

Cited by 32 publications

References 50 publications

Apolipoprotein CIII and diabetes. Is there a link?

Apolipoprotein CIII and diabetes. Is there a link?

Endoplasmic Reticulum Stress of Skeletal Muscle and Exercise Training Effects in Aging and Obesity

Denitrase activity of Debaryomyces�hansenii reduces the oxidized compound 3‑nitrotyrosine in mice liver with colitis

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