Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice

Trevaskis, James L.; Griffin, Peter S.; Wittmer, Carrie; Neuschwander‐Tetri, Brent A.; Brunt, Elizabeth M.; Dolman, Carrie S.; Erickson, Michelle A.; Napora, James; Parkes, David G.; Roth, Jonathan D.

doi:10.1152/ajpgi.00476.2011

Cited by 231 publications

(226 citation statements)

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“…This is in line with recent findings by Clapper et al [6] and Honda et al [24] in C57 AMLN mice, thus supporting the wild-type C57 DIO-NASH mouse as a suitable preclinical model for dietinduced obesity and NASH. In addition, the genetically obese ob/ob mouse model was also recently demonstrated to exhibit fibrotic NASH when fed AMLN diet [11,25] . In the leptin-deficient model superimposing the NASH diet high in trans-fat, fructose and cholesterol represents a "second hit" in development of preclinical NASH.…”

Section: Discussionmentioning

confidence: 99%

“…) are predisposed to develop steatohepatitis, however, when maintained on regular rodent chow they do not develop fibrosis [11] . In fact, it was previously postulated that Lep ob /Lep ob mice are incapable of developing hepatic fibrosis [9] .…”

Section: Obmentioning

confidence: 99%

“…In fact, it was previously postulated that Lep ob /Lep ob mice are incapable of developing hepatic fibrosis [9] . This notion was dispelled by the observation that Lep ob /Lep ob mice maintained on the AMLN diet for at least 12 wk do in fact develop the key hallmarks of NASH, including fibrosis [11] . The present study assessed key NASH diagnostic characteristics (e.g., steatosis score, inflammation, ballooning degeneration and fibrosis stage), metabolic endpoints and gene expression signatures in wild-type C57Bl/6J and Lep ob /Lep ob mice, fed the AMLN diet for a total of 34 and 20 wk, respectively, including an eightweek repeated vehicle dosing period.…”

Section: Obmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Recently, a novel wild-type diet-induced obese fibrotic NASH mouse model was introduced by Trevaskis et al [11] , based on the ALIOS diet model [12] . This model, generated by feeding an ad libitum diet high in trans-fat, fructose and cholesterol to wild-type C57Bl/6J mice [the Amylin liver NASH model (AMLN)], displayed key hallmarks of clinical NASH [11] . The AMLN mouse model was further optimized by demonstrating a liver biopsy technique for assessing individual steatosis, inflammation, ballooning degeneration and fibrosis staging, prior to a putative study intervention [6] .…”

Section: Introductionmentioning

confidence: 99%

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Obese diet-induced mouse models of nonalcoholic steatohepatitis-tracking disease by liver biopsy

Kristiansen¹,

Veidal²,

Rigbolt³

et al. 2016

WJH

108

156

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Author contributions: Kristiansen MNB, Veidal SS, Rigbolt KTG, Tølbøl KS and Feigh M performed the experiments and analyzed the data; Rigbolt KTG performed the molecular investigations; Kristiansen MNB and Veidal SS performed the histological analysis; Veidal SS, Rigbolt KTG, Roth JD, Jelsing J, Vrang N and Feigh M designed and coordinated the research; Kristiansen MNB, Veidal SS, Rigbolt KTG, Tølbøl KS, Roth JD, Jelsing J, Vrang N and Feigh M wrote the paper.Institutional review board statement: This study includes no data or material from patients. We confirm that all of the required permissions for this study were obtained from our local authorities as mentioned in the Institutional animal care and use committee statement.Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Danish Committee for animal research and covered by a personal license for Jacob Jelsing (2013-15-2934-00784). All of the institutional and national guidelines for the care and use of laboratory animals were followed.Conflict-of-interest statement: There are no patents, products in development or marked products to declare. Abstract AIM: To characterize development of diet-induced nonalcoholic steatohepatitis (NASH) by performing liver biopsy in wild-type and genetically obese mice. METHODS:Male wild-type C57BL/6J (C57) mice (DIO-NASH) and male Lep ob /Lep ob (ob /ob ) mice (ob /ob -NASH) were maintained on a diet high in trans-fat (40%), fructose (22%) and cholesterol (2%) for 26 and 12 wk, respectively. A normal chow diet served as control in C57 mice (lean chow) and ob /ob mice (ob /ob chow).After the diet-induction period, mice were liver biopsied and a blinded histological assessment of steatosis and fibrosis was conducted. Mice were then stratified into groups counterbalanced for steatosis score and fibrosis stage and continued on diet and to receive daily PO dosing of vehicle for 8 wk. Global gene expression in liver tissue was assessed by RNA sequencing and bioinformatics. Metabolic parameters, plasma liver enzymes and lipids (total cholesterol, triglycerides) as well as hepatic lipids and collagen content were measured by biochemical analysis. Non-alcoholic fatty liver disease activity score (NAS) (steatosis/inflammation/ballooning Obese diet-induced mouse models of nonalcoholic steatohepatitis-tracking disease by liver biopsy Basic Study ORIGINAL ARTICLEdegeneration) and fibrosis were scored. Steatosis and fibrosis were also quantified using percent fractional area. RESULTS: Diet-induction for 26 and 12 wk in DIO-NASH and ob /ob -NASH mice, respectively, elicited progressive metabolic perturbations characterized by increased adiposity, total cholesterol and elevated plasma liver enzymes. The diet also induced clear histological features of NASH including hepatosteatosis and fibrosis. Overall, the metabolic NASH phenotype was more pronounced in ob /ob -NASH vs DIO-NASH mice. During the eight week repeated vehicle dosing period, the metabolic phenotype was sustai...

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Section: Discussionmentioning

confidence: 99%

Section: Obmentioning

confidence: 99%

Section: Obmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Obese diet-induced mouse models of nonalcoholic steatohepatitis-tracking disease by liver biopsy

Kristiansen¹,

Veidal²,

Rigbolt³

et al. 2016

WJH

108

156

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Inhibition of MGAT2 modulates fat‐induced gut peptide release and fat intake in normal mice and ameliorates obesity and diabetes in ob/ob mice fed on a high‐fat diet

et al. 2020

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Monoacylglycerol O‐acyltransferase 2 (MGAT2) is one of the key enzymes responsible for triglyceride (TG) re‐synthesis in the small intestine. We have previously demonstrated that pharmacological inhibition of MGAT2 has beneficial effects on obesity and metabolic disorders in mice. Here, we further investigate the effects of MGAT2 inhibition on (a) fat‐induced gut peptide release and fat intake in normal mice and (b) metabolic disorders in high‐fat diet (HFD)‐fed ob/ob mice, a model of severe obesity and type 2 diabetes mellitus, using an orally bioavailable MGAT2 inhibitor Compound B (CpdB). CpdB inhibited elevation of plasma TG in mice challenged with an oil‐supplemented liquid meal. Oil challenge stimulated the secretion of two gut anorectic hormones (peptide tyrosine–tyrosine and glucagon‐like peptide‐1) into the bloodstream, and these responses were augmented in mice pretreated with CpdB. In a two‐choice test using an HFD and a low‐fat diet, CpdB selectively inhibited intake of the HFD in normal mice. Administration of CpdB to HFD‐fed ob/ob mice for 5 weeks suppressed food intake and body weight gain and inhibited elevation of glycated hemoglobin. These results indicate that pharmacological MGAT2 inhibition modulates fat‐induced gut peptide release and fat intake in normal mice and improves obesity and diabetes in HFD‐fed ob/ob mice and thus may have potential for development into a treatment of obesity and its related metabolic diseases.

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Molecular antagonists, leptin or other hormones in supplementing environmental factors?

Hazlehurst

Tomlinson

2016

Clinical Dilemmas in Non‐Alcoholic Fatty Liver Disease

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Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice

Abstract: Trevaskis JL, Griffin PS, Wittmer C, Neuschwander-Tetri BA, Brunt EM, Dolman CS, Erickson MR, Napora J, Parkes DG, Roth JD. Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice.

Cited by 231 publications

References 44 publications

Obese diet-induced mouse models of nonalcoholic steatohepatitis-tracking disease by liver biopsy

Obese diet-induced mouse models of nonalcoholic steatohepatitis-tracking disease by liver biopsy

Inhibition of MGAT2 modulates fat‐induced gut peptide release and fat intake in normal mice and ameliorates obesity and diabetes in ob/ob mice fed on a high‐fat diet

Molecular antagonists, leptin or other hormones in supplementing environmental factors?

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