Obese mice weight loss role on nonalcoholic fatty liver disease and endoplasmic reticulum stress treated by a GLP-1 receptor agonist

Pontes-da-Silva, Rayane Miranda; Marinho, Thatiany de Souza; Cardoso, Luiz E.M.; Mandarim-de-Lacerda, Carlos Alberto; Águila, Márcia Barbosa

doi:10.1038/s41366-021-00955-7

Cited by 37 publications

(36 citation statements)

References 67 publications

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“…163 Of note, semaglutide lessened liver glucose uptake and ER stress by reducing ATF4, CHOP, and GADD34 mRNA expression, with the reduction of GADD45 mRNA expression being independent of weight loss. 163 From another point of view, substances that alleviate ER stress can prove useful in treating NAFLD/NASH. Chemical chaperones (e.g., the 4-phenyl butyric acid; PBA) which can increase protein folding capacity and thereby reduce ER stress, and endogenous bile acids and derivatives (e.g., the tauroursodeoxycholic acid; TUD-CA), that modulate ER stress have been found to reduce inflammation, apoptosis, and necrosis and improve liver regeneration in steatotic and nonsteatotic livers during partial hepatectomy under ischemia-reperfusion.…”

Section: Implications For Nafld Treatmentmentioning

confidence: 96%

“…Exendin‐4 treatment was shown to be more significant in 148I/I cells than in 148M/M cells in terms of reducing the intrahepatic fat content and inhibiting ER stress‐related inflammation, since the upregulated protein expressions of BiP and total IRE1α, caused by palmitic acid treatment, were markedly inhibited by exendin‐4 in PNPLA3 148I/I HepG2 cells but remained unchanged in PNPLA3 148M/M HepG2 cells 162 . Semaglutide reduced energy consumption leading to weight loss and improved glucose intolerance, glycated hemoglobin, insulin resistance/sensitivity, plasma lipids, improved hormones such as gastric inhibitory polypeptide and adipokines, reduced lipogenesis and inflammation, increased β‐oxidation and mitigated liver steatosis in wild‐type mice fed an HFD 163 . Of note, semaglutide lessened liver glucose uptake and ER stress by reducing ATF4, CHOP , and GADD34 mRNA expression, with the reduction of GADD45 mRNA expression being independent of weight loss 163 …”

Section: Implications For Nafld Treatmentmentioning

confidence: 99%

“…Semaglutide reduced energy consumption leading to weight loss and improved glucose intolerance, glycated hemoglobin, insulin resistance/sensitivity, plasma lipids, improved hormones such as gastric inhibitory polypeptide and adipokines, reduced lipogenesis and inflammation, increased β‐oxidation and mitigated liver steatosis in wild‐type mice fed an HFD 163 . Of note, semaglutide lessened liver glucose uptake and ER stress by reducing ATF4, CHOP , and GADD34 mRNA expression, with the reduction of GADD45 mRNA expression being independent of weight loss 163 …”

Section: Implications For Nafld Treatmentmentioning

confidence: 99%

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Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD)

Flessa

Kyrou

Nasiri-Ansari

et al. 2022

J of Cellular Biochemistry

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Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation in the absence of excessive alcohol consumption and is strongly associated with obesity, type 2 diabetes (T2DM) and other metabolic syndrome features. NAFLD is becoming increasingly prevalent and currently constitutes the leading cause of hepatocellular carcinoma (HCC). Recently, the term metabolic (dysfunction) associated fatty liver disease (MAFLD) has been proposed reflecting more accurately the underlying pathogenesis and the cardiometabolic disorders associated to NAFLD/MAFLD. Given the vital metabolic functions of the liver to maintain the body homeostasis, an extended endoplasmic reticulum (ER) network is mandatory in hepatocytes to retain its capacity to adapt to the multiple extracellular and intracellular signals mediating metabolic changes. Dysfunction of hepatocyte ER homeostasis and disturbance of its interaction with mitochondria have been recognized to be involved in the NAFLD pathophysiology. Apart from hepatocytes, hepatic stellate cells, and Kupffer cells have been shown to play an important role in the occurrence of NAFLD and progression to nonalcoholic steatohepatitis (NASH) with possibly different roles in the different stages of the NAFLD spectrum. Furthermore, excess lipid accumulation in the liver causes lipotoxicity which interacts with ER stress and culminates in inflammation and hepatocellular damage, mechanisms crucially implicated in NASH pathogenesis. Finally, the circadian clock machinery regulates ER stress‐related pathways and vice versa, thus controlling the homeostasis of the liver metabolism and being implicated in the NAFLD progression. This review presents a comprehensive overview of the current knowledge supporting the impact of ER stress signaling on NAFLD, whilst summarizing potential therapeutic interventions targeting this process.

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Section: Implications For Nafld Treatmentmentioning

confidence: 96%

Section: Implications For Nafld Treatmentmentioning

confidence: 99%

Section: Implications For Nafld Treatmentmentioning

confidence: 99%

See 1 more Smart Citation

Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD)

Flessa

Kyrou

Nasiri-Ansari

et al. 2022

J of Cellular Biochemistry

View full text Add to dashboard Cite

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“…One of the successful pharmacological approaches seems to be using of glucagon-like peptide-1 receptor (GLP1R) to improve metabolism and modest lowering body weight [ 107 ]. In obese mice, treatment with semaglutide, a GLP1R agonist, led to consequent weight loss, reduced liver inflammation, insulin resistance, and stress of endoplasmic reticulum [ 108 , 109 ]. Currently, semaglutide is approved by European Medicines Agency and the Food and Drug Administration for the treatment of type 2 diabetes mellitus and is ongoing clinical trials as antiobesity drug [ 107 ].…”

Section: Strategies For the Prevention Of Metabolic Syndromementioning

confidence: 99%

Metabolic Syndrome: Lessons from Rodent and Drosophila Models

Vatashchuk

Bayliak

Hurza

et al. 2022

BioMed Research International

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Overweight and obesity are health conditions tightly related to a number of metabolic complications collectively called “metabolic syndrome” (MetS). Clinical diagnosis of MetS includes the presence of the increased waist circumference or so-called abdominal obesity, reduced high density lipoprotein level, elevated blood pressure, and increased blood glucose and triacylglyceride levels. Different approaches, including diet-induced and genetically induced animal models, have been developed to study MetS pathogenesis and underlying mechanisms. Studies of metabolic disturbances in the fruit fly Drosophila and mammalian models along with humans have demonstrated that fruit flies and small mammalian models like rats and mice have many similarities with humans in basic metabolic functions and share many molecular mechanisms which regulate these metabolic processes. In this paper, we describe diet-induced, chemically and genetically induced animal models of the MetS. The advantages and limitations of rodent and Drosophila models of MetS and obesity are also analyzed.

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“…[15][16][17] Current studies about semaglutide focus on cardiovascular disease and non-alcoholic fatty liver disease. 16,[18][19][20] However, the renoprotective effect of semaglutide and its involved mechanisms remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Metabolomics Provides Insights into Renoprotective Effects of Semaglutide in Obese Mice

Chen¹,

Chen²,

Ren³

et al. 2022

DDDT

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Semaglutide, a new long-acting glucagon-like peptide-1 analogue, has shown benefits for renal diseases, but its direct role on kidney metabolism under obesity remains unclear. The study aims to elucidate the protective effect and metabolic modulation mechanism of semaglutide on obesity-related kidney injury. Methods: Male C57BL/6J mice were divided into control and obesity groups. Mice in the obesity group had a high-fat diet and were treated with or without semaglutide (30nmol/kg/day). The study assayed blood biochemistry and then evaluated renal pathological injury through Periodic Acid-Schiff staining and electron microscopy. Metabolomics was utilized to analyze obesity-related metabolites in kidney samples. Results: Semaglutide significantly improved glucose homeostasis, insulin resistance, and kidney injury in obese mice. We successfully identified 377 altered metabolites (P<0.05). It was suggested that semaglutide directly improved oxidative stress and inflammation-related metabolites such as nicotinamide adenine dinucleotide (NAD + ) and adenosine in the kidney of obese mice, which have not been documented in obesity-related kidney injury. Relevant enriched pathways were included phospholipids and lysophospholipids metabolism, purine metabolism, NAD + metabolism, and insulin resistance-related metabolism. They could serve as potential targets for intervention of obesity-related kidney injury. Conclusion:Our study revealed the metabolomics-based renoprotective mechanism of semaglutide in obese mice for the first time. The innovation lied in the identified metabolites such as NAD + and adenosine targeted by semaglutide, which have not been documented in obesity-related kidney injury. Semaglutide may be a promising therapy for obesity-related kidney diseases.

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Obese mice weight loss role on nonalcoholic fatty liver disease and endoplasmic reticulum stress treated by a GLP-1 receptor agonist

Cited by 37 publications

References 67 publications

Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD)

Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD)

Metabolic Syndrome: Lessons from Rodent and Drosophila Models

Metabolomics Provides Insights into Renoprotective Effects of Semaglutide in Obese Mice

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