Glucagon‐like peptide‐1 preserves non‐alcoholic fatty liver disease through inhibition of the endoplasmic reticulum stress‐associated pathway

Ao, Na; Yang, Jing; Wang, Xiaochen; Du, Juan

doi:10.1111/hepr.12551

Cited by 45 publications

(46 citation statements)

References 38 publications

(46 reference statements)

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“…Previous studies from our laboratory have recorded that the high‐fat feeding regime also applied in the current study does not induce excessive weight gain compared to chow, nor promotes excessive deposition of body fat compared to chow‐fed controls, confirming the guinea pig as a non‐obese (lean) animal model of NAFLD and NASH . The present findings indicate that liraglutide exerts similar effects on NASH histopathology in lean guinea pigs as previously reported in clinical and pre‐clinical settings utilizing obese individuals and animals . Notably, the beneficial effects of treatment with liraglutide occurred in the presence of severe (grade 3) fibrosis.…”

Section: Discussionsupporting

confidence: 87%

“…However, the absence of hepatocyte GLP‐1 receptors implies that histological improvements are mediated by indirect effects of liraglutide . Studies in obese murine NASH models have suggested that liraglutide decreases endoplasmic reticulum stress and TNF‐α levels in the liver, both of which are believed to play key roles in NASH . It remains to be investigated if similar mechanisms underlie the effect of liraglutide in lean NASH.…”

Section: Discussionmentioning

confidence: 99%

“…Feed aliquots were thawed twice weekly and food intake measured by weighing the amount of food remaining prior to each refill. The dose of liraglutide (Novo Nordisk A/S, Måløv, Denmark) was based on previous literature and a small pilot study aiming to induce a 10–15% weight loss. Liraglutide was slowly titrated over a period of 9 days to 30 nmol/kg body‐weight (BW) twice a day (BID) and administered by subcutaneous injections.…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, much of the current clinical and pre‐clinical research largely targets obese NASH, potentially neglecting the lean NASH phenotype. Glucagon‐like peptide 1 (GLP‐1) receptor agonists may hold promise as potential pharmacological treatment options and have been found to improve both hepatic steatosis and oxidative stress in obese mice and rats with steatosis or mild (no/early stage fibrosis) NASH . In human beings, an investigator‐initiated, randomized, controlled clinical trial recently reported histological resolution of NASH in obese/overweight patients treated for 48 weeks with the GLP‐1 receptor agonist liraglutide .…”

mentioning

confidence: 99%

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Liraglutide Decreases Hepatic Inflammation and Injury in Advanced Lean Non‐Alcoholic Steatohepatitis

Ipsen

Rolin

Rakipovski

et al. 2018

Basic Clin Pharma Tox

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Although commonly associated with obesity, non-alcoholic fatty liver disease (NAFLD) is also present in the lean population representing a unique disease phenotype. Affecting 25% of the world's population, NAFLD is associated with increased mortality especially when progressed to non-alcoholic steatohepatitis (NASH). However, no approved pharmacological treatments exist. Current research focuses mainly on NASH associated with obesity, leaving the effectiveness of promising treatments in lean NASH virtually unknown. This study therefore aimed to evaluate the effect of liraglutide (glucagon-like peptide 1 analogue) and dietary intervention, alone and in combination, in guinea pigs with non-obese NASH. After 20 weeks of high-fat feeding (20% fat, 15% sucrose, 0.35% cholesterol), 40 female guinea pigs were block-randomized based on weight into four groups receiving one of four treatments for 4 weeks: continued high-fat diet (HF, control), high-fat diet and liraglutide treatment (HFL), chow diet (4% fat, 0% sucrose, 0% cholesterol; HFC) or chow diet and liraglutide treatment (HFCL). High-fat feeding induced NASH with severe fibrosis. Liraglutide decreased inflammation (p < 0.05) and hepatocyte ballooning (p < 0.05), while increasing hepatic α-tocopherol (p = 0.0154). Dietary intervention did not improve liver histopathology significantly, but decreased liver weight (p = 0.004), plasma total cholesterol (p = 0.0175), LDL-cholesterol (p = 0.0063), VLDL-cholesterol (p = 0.0034), hepatic cholesterol (p < 0.0001) and increased hepatic vitamin C (p = 0.0099). Combined liraglutide and dietary intervention induced a rapid weight loss, necessitating periodical liraglutide dose adjustment/discontinuation, limiting the strength of the findings from this group. Collectively, this pre-clinical study supports the beneficial effect of liraglutide on NASH and extends this notion to lean NASH.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Liraglutide Decreases Hepatic Inflammation and Injury in Advanced Lean Non‐Alcoholic Steatohepatitis

Ipsen

Rolin

Rakipovski

et al. 2018

Basic Clin Pharma Tox

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“…The beneficial effects on hepatic lipid accumulation and on metabolic parameters in fatty liver disease seem to be because of reduced inflammation and endoplasmic reticulum stress [50]. The antioxidative and anti-inflammatory effects were also associated with an inactivation of the proinflammatory c-Jun N-terminal kinase pathway [49 & ].…”

Section: Effect Of Glucagon-like Peptide-1 To Improve Hepatic Steatosismentioning

confidence: 99%

Glucagon-like peptide-1, glucagon-like peptide-2, and lipid metabolism

Lutz¹,

Osto

2016

Current Opinion in Lipidology

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PURPOSE OF REVIEW: Glucagon-like peptide-1 (GLP-1) is the best known incretin hormone able to potentiate glucose-induced insulin secretion. Moreover, GLP-1 is currently under intensive investigation as a potential crucial mediator of beneficial metabolic effects after bariatric surgery, because of its eating inhibitory, antiobesity, and antidiabetes effects. This review briefly summarizes recent findings on the specific effects of GLP-1 on lipoprotein metabolism. The related hormone GLP-2 is derived from the same precursor gene; its effects on lipoprotein metabolism will also be discussed briefly. RECENT FINDINGS: Pharmacological activation of the GLP-1 system has beneficial effects on obesity-induced alterations of lipoprotein metabolism. These benefits can be observed with direct GLP-1 receptor agonists like liraglutide or exendin-4, but also with inhibitors of dipeptidyl peptidase IV (DPP-IV), which reduce the breakdown of endogenous GLP-1. The role of GLP-2-related pathways on lipid levels and metabolism are less clear, but some effects (e.g. increased intestinal chylomicron output) are opposite to GLP-1. SUMMARY: Activation of the GLP-1-dependent pathways may perhaps translate into a lower cardiovascular risk. Understanding how GLP-1 and GLP-2 regulate and interact in the control of lipoprotein metabolism will set the stage for the development of new strategies to treat dyslipidaemia in obesity, diabetes, and other cardiometabolic diseases. Purpose of review Glucagon-like peptide-1 (GLP-1) is the best known incretin hormone able to potentiate glucose-induced insulin secretion. Moreover, GLP-1 is currently under intensive investigation as a potential crucial mediator of beneficial metabolic effects after bariatric surgery, because of its eating inhibitory, antiobesity, and antidiabetes effects. This review briefly summarizes recent findings on the specific effects of GLP-1 on lipoprotein metabolism. The related hormone GLP-2 is derived from the same precursor gene; its effects on lipoprotein metabolism will also be discussed briefly. Recent findingsPharmacological activation of the GLP-1 system has beneficial effects on obesity-induced alterations of lipoprotein metabolism. These benefits can be observed with direct GLP-1 receptor agonists like liraglutide or exendin-4, but also with inhibitors of dipeptidyl peptidase IV (DPP-IV), which reduce the breakdown of endogenous GLP-1. The role of GLP-2-related pathways on lipid levels and metabolism are less clear, but some effects (e.g. increased intestinal chylomicron output) are opposite to GLP-1. SummaryActivation of the GLP-1-dependent pathways may perhaps translate into a lower cardiovascular risk. Understanding how GLP-1 and GLP-2 regulate and interact in the control of lipoprotein metabolism will set the stage for the development of new strategies to treat dyslipidaemia in obesity, diabetes, and other cardiometabolic diseases.

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A Novel Interacting Protein SERP1 Regulates the N‐Linked Glycosylation and Function of GLP‐1 Receptor in the Liver

Xiao

Han

Wang

et al. 2017

J of Cellular Biochemistry

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Glucagon-like peptide 1 (GLP-1) exerts multiple effects on metabolism through its receptor, GLP-1R, in the liver. Activation and transduction of GLP-1R require complex interactions of largely unknown accessory proteins, and these processes are crucial to the response to endoplasmic reticulum (ER) stress. Using the membrane-based split ubiquitin yeast two-hybrid system (MYTH) and a human liver cDNA library, we obtained the human GLP-1R interactome and identified SERP1 as a potential interacting protein based on its ability to stabilize membrane proteins and facilitate N-linked glycosylation. GLP-1R and SERP1 were co-expressed in HEK-293 cells, and their interaction was confirmed by co-immunoprecipitation. We then found that overexpression of SERP1 could rescue GLP-1R glycosylation after application of tunicamycin to block N-linked glycosylation. SERP1 overexpression also attenuated exendin-4-stimulated cAMP accumulation and AMPK activation. However, the glycosylation and function of mutant GLP-1R, in which all three sites for N-linked glycosylation were mutated, were not increased with overexpression of SERP1. Moreover, as a GLP-1R interactor, SERP1 could also partly reverse the accumulation of tunicamycin-induced ER stress. Taken together, our findings identify a group of proteins that interact with GLP-1R and show that one specific interacting protein, SERP1, has an important role in facilitating the glycosylation of GLP-1R and rescuing its activities after ER stress induced by tunicamycin. J. Cell. Biochem. 118: 3616-3626, 2017. © 2017 Wiley Periodicals, Inc.

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Glucagon‐like peptide‐1 preserves non‐alcoholic fatty liver disease through inhibition of the endoplasmic reticulum stress‐associated pathway

Abstract: GLP-1 protected against NAFLD by inactivating the ER stress-associated apoptosis pathway. In addition, the effect was possibly related to the signaling pathway of ERp46.

Cited by 45 publications

References 38 publications

Liraglutide Decreases Hepatic Inflammation and Injury in Advanced Lean Non‐Alcoholic Steatohepatitis

Liraglutide Decreases Hepatic Inflammation and Injury in Advanced Lean Non‐Alcoholic Steatohepatitis

Glucagon-like peptide-1, glucagon-like peptide-2, and lipid metabolism

A Novel Interacting Protein SERP1 Regulates the N‐Linked Glycosylation and Function of GLP‐1 Receptor in the Liver

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