SIRT1/HSF1/HSP pathway is essential for exenatide‐alleviated, lipid‐induced hepatic endoplasmic reticulum stress

Zheng, Xiaobin; Xu, Fen; Liang, Hua; Cao, Huanyi; Cai, Mengyin; Xu, Wen; Weng, Jianping

doi:10.1002/hep.29238

Cited by 76 publications

(58 citation statements)

References 47 publications

(115 reference statements)

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“…Glucagon‐like peptide‐1 receptor agonists have a beneficial effect on attenuating hepatic steatosis, but the exact mechanisms have not been clearly defined . Recent studies reported that Sirt1 could be a crucial mediator for GLP‐1Ra‐mediated NAFLD, but they did not show how GLP‐1Ras modulate Sirt1 to attenuate fatty liver . We found that liraglutide upregulated the expression of ATGL and Sirt1 to antagonize lipid accumulation in vivo and in vitro .…”

Section: Discussioncontrasting

confidence: 57%

“…S1d–f). Depending on the regulation of ATGL, Sirt1 mediates the role of GLP‐1Ra in hepatic steatosis in HFD‐induced WT mice . Therefore, liraglutide could mitigate intracellular lipids by regulating the ATGL/Sirt1 signaling pathway.…”

Section: Resultsmentioning

confidence: 99%

“…Presenting on human hepatocytes, GLP‐1 receptor exerted its function in preventing lipid accumulation in hepatocytes . It also protects against lipid‐induced endoplasmic reticulum (ER) stress and hepatic steatosis in HFD‐induced mice through upregulation of sirtuin 1 (Sirt1) expression . Interestingly, ATGL regulated hepatic lipid droplet catabolism and FA oxidation mainly through the activation of autophagy/lipophagy by Sirt1 .…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of microRNA‐124a attenuates non‐alcoholic fatty liver disease through upregulation of adipose triglyceride lipase and the effect of liraglutide intervention

Fang

Shen

et al. 2019

Hepatology Research

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Aim Glucagon‐like peptide‐1 receptor agonists (GLP‐1Ras) have been reported to prevent non‐alcoholic fatty liver disease (NAFLD), but the potential mechanisms are still debated. MicroRNAs (miRNAs) play a prominent role in the field of metabolic disorders, including NAFLD. Our study was designed to further evaluate the effect of GLP‐1Ra liraglutide on NAFLD in terms of miRNAs. Methods MicroRNA expression was evaluated by clustering analysis of microRNA arrays in high fat diet‐fed mice. The luciferase reporter assay was carried out to validate the cross‐talk between adipose triglyceride lipase (ATGL) and miR‐124a. MicroRNA‐124a mimics and inhibitor plasmids were transfected to study the role of miR‐124a in palmitate‐treated normal human liver cell line (HL‐7702). Liraglutide treatment was used to observe the effect of GLP‐1Ra on the miR‐124a/ATGL pathway. Results Expression of ATGL decreased and miR‐124a expression increased in hepatosteatosis in vivo and in vitro. Mechanistically, miR‐124a interacted with the 3′‐untranslated region of ATGL mRNA and induced its degradation. MicroRNA‐124a overexpression antagonized the effect of liraglutide on NAFLD by inhibiting ATGL expression, whereas miR‐124a knockdown led to elevated ATGL and sirtuin 1 (Sirt1) expression, and subsequently decreased lipid accumulation and inflammation in cells. Conclusions MicroRNA‐124a overexpression contributes to the progression of NAFLD through reduction of ATGL expression, whereas miR‐124a knockdown can reverse this trend, suggesting that miR‐124a and its downstream target ATGL can be novel therapeutic targets of NAFLD. We reveal a novel mechanism by which liraglutide attenuates NAFLD by the miR‐124a/ATGL/Sirt1 pathway.

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Section: Discussioncontrasting

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of microRNA‐124a attenuates non‐alcoholic fatty liver disease through upregulation of adipose triglyceride lipase and the effect of liraglutide intervention

Fang

Shen

et al. 2019

Hepatology Research

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“…Hepatic messenger RNA (mRNA) expression of several ER stress markers were analyzed for the HFD and HFD + VC groups. Sirtuin 1 ( Sirt1 ) has recently been shown to be a negative regulator of ER stress . Indeed, here VC significantly decreased Sirt1 expression compared to the HFD controls.…”

Section: Resultsmentioning

confidence: 71%

Vinyl chloride dysregulates metabolic homeostasis and enhances diet‐induced liver injury in mice

Lang

Chen

Poff

et al. 2018

Hepatology Communications

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Vinyl chloride (VC), a common industrial organochlorine and environmental pollutant, has been shown to directly cause hepatic angiosarcoma and toxicant‐associated steatohepatitis at high exposure levels. However, the impact of lower concentrations of VC on the progression of underlying liver diseases (e.g., nonalcoholic fatty liver disease [NAFLD]) is unclear. Given the high prevalence of NAFLD in the United States (and worldwide) population, this is an important concern. Recent studies by our group with VC metabolites suggest a potential interaction between VC exposure and underlying liver disease to cause enhanced damage. Here, a novel mouse model determined the effects of VC inhalation at levels below the current Occupational Safety and Health Administration limit (<1 ppm) in the context of NAFLD to better mimic human exposure and identify potential mechanisms of VC‐induced liver injury. VC exposure caused no overt liver injury in mice fed a low‐fat diet. However, in mice fed a high‐fat diet (HFD), VC significantly increased liver damage, steatosis, and increased neutrophil infiltration. Moreover, VC further enhanced HFD‐induced oxidative and endoplasmic reticulum stress. Importantly, VC exposure dysregulated energy homeostasis and impaired mitochondrial function, even in mice fed a low‐fat diet. In toto, the results indicate that VC exposure causes metabolic stress that sensitizes the liver to steatohepatitis caused by HFD. Conclusion: The hypothesis that low‐level (below the Occupational Safety and Health Administration limit) chronic exposure to VC by inhalation enhances liver injury caused by an HFD is supported. Importantly, our data raise concerns about the potential for overlap between fatty diets (i.e., Western diet) and exposure to VC and the health implications of this co‐exposure for humans. It also emphasizes that current safety restrictions may be insufficient to account for other factors that can influence hepatotoxicity. (Hepatology Communications 2018;2:270‐284)

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“…Downregulation of SIRT1 has been suggested to cause a vascular/endothelial ERS [60]. The SIRT1 pathway has also been shown to play an essential role in the exenatide-induced alleviation of the lipid-induced ERS and hepatic steatosis [61]. In addition, Kang, X. et al reported that SIRT1 inhibition mainly induced the PERK-eIF-2alpha-CHOP axis of the ERS response in the growth-plate chondrocytes, while the EX527 or SIRT1 siRNA-mediated inhibition of metatarsal growth and growth-plate chondrogenesis was partly neutralized by a chemical chaperone that attenuates the ERS [62].…”

Section: Discussionmentioning

confidence: 99%

Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study

Yan

Long²,

Wei

et al. 2020

BMC Ophthalmol

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Background: Retinitis pigmentosa (RP) is a kind of inherited retinal degenerative diseases characterized by the progressive loss of photoreceptors. RP has been a conundrum without satisfactory countermeasures in clinic until now. Acetaldehyde dehydrogenase 2 (ALDH2), a major enzyme involved in aldehyde detoxification, has been demonstrated to be beneficial for a growing number of human diseases, such as cardiovascular dysfunction, diabetes mellitus and neurodegeneration. However, its protective effect against RP remains unknown. Our study explored the impact of ALDH2 on retinal function and structure in N-methyl-N-nitrosourea (MNU)-induced RP rats. Methods: Rats were gavaged with 5 mg/kg Alda-1, an ALDH2 agonist, 5 days before and 3 days after MNU administration. Assessments of retinal function and morphology as well as measurement of specific proteins expression level were conducted. Results: Electroretinogram recordings showed that Alda-1 administration alleviated the decrease in amplitude caused by MNU, rendering protection of retinal function. Mitigation of photoreceptor degeneration in MNU-treated retinas was observed by optical coherence tomography and retinal histological examination. In addition, Western blotting results revealed that ALDH2 protein expression level was upregulatedwith increased expression of SIRT1 protein after the Alda-1 intervention. Besides, endoplasmic reticulum stress (ERS) was reduced according to the significant downregulation of GRP78 protein, while apoptosis was ameliorated as shown by the decreased expression of PARP1 protein.Conclusions: Together, our data demonstrated that ALDH2 could provide preservation of retinal function and morphology against MNU-induced RP, with the underlying mechanism at least partly related to the modulation of SIRT1, ERS and apoptosis.

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SIRT1/HSF1/HSP pathway is essential for exenatide‐alleviated, lipid‐induced hepatic endoplasmic reticulum stress

Cited by 76 publications

References 47 publications

Inhibition of microRNA‐124a attenuates non‐alcoholic fatty liver disease through upregulation of adipose triglyceride lipase and the effect of liraglutide intervention

Inhibition of microRNA‐124a attenuates non‐alcoholic fatty liver disease through upregulation of adipose triglyceride lipase and the effect of liraglutide intervention

Vinyl chloride dysregulates metabolic homeostasis and enhances diet‐induced liver injury in mice

Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study

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