When GLP-1 hits the liver: a novel approach for insulin resistance and NASH

Abstract

Editorial FocusWhen GLP-1 hits the liver: a novel approach for insulin resistance and NASHYong Ook Kim, and Detlef SchuppanYong Ook KimMolecular and Translational Medicine, Dept. of Medicine I, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany, and Detlef SchuppanMolecular and Translational Medicine, Dept. of Medicine I, University Medical Center, Johannes Gutenberg University Mainz, Mainz, GermanyPublished Online:15 Apr 2012https://doi.org/10.1152/ajpgi.00078.2012This is the final version - click for previous versionMoreSectionsPDF (614 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to steatohepatitis (NASH), increasing fibrosis and eventually, cirrhosis (22). Importantly, NASH accompanied by fibrosis and severe inflammation is the most relevant predictor for disease progression to cirrhosis and hepatocellular carcinoma (21). NAFLD is tightly associated with obesity, insulin resistance (IR), and overt type 2 diabetes (T2D) and represents a manifestation and driver of the metabolic syndrome (5, 7, 20). While the best therapy to improve insulin sensitivity is diet combined with exercise, these are difficult to achieve for the majority of patients, requiring at least adjunctive pharmacological therapies (5, 20). A novel class of pharmacological agents that appear to be devoid of unwanted side effects, including weight gain, are drugs that increase the action of glucagon-like peptide-1 (GLP-1) directly (GLP-1 mimetics, such as exenatide) or indirectly via inhibition of dipeptidyl peptidase-4 (DPP-4), an enzyme that is ubiquitously expressed on the cell surface and that rapidly degrades GLP-1 to an inactive peptide. Exenatide and DPP-4 inhibitors have been widely validated to treat T2D, and their potential to effectively treat NAFLD and NASH attracts increasing attention (8, 22, 23). Moreover, experimental models that mimic human NAFLD and especially NASH are constantly improved to serve as a preclinical platform to evaluate novel therapeutic strategies. Mouse models of NAFLD are based on genetic mutations, such as ob/ob or db/db mice, or diet, such as the methionine/choline-deficient (MCD) diet (1). However, none of these fully reflect the phenotype of human NAFLD and especially NASH. The more recent models that exploit either a high-fat/trans-fat-enriched and high fructose diet (28) diet, or a high-fat diet with low-dose streptozotocin (which induces mild insulin deficiency not matching insulin demand) (14) much better resemble human NASH pathogenesis and histopathology including fibrosis.The study by Trevaskis et al. (29) examined another modification of these novel NASH models, i.e., mice deficient in leptin-signaling (ob/ob) or their wild-type controls fed a high trans-fat (HTF), high fructose, and high cholesterol diet. The authors also assessed the beneficial effect the GLP-1R agonist AC3174 in this model. They found that ob/ob mice fed this diet developed more severe pathophysiologic features of fibrotic NASH than wild-type mice. This is unexpected, since intact leptin signaling is considered important for the activation of fibrogenic hepatic stellate cells and myofibroblasts (here jointly termed HSC) (10), and leptin deficient ob/ob mice are resistant to hepatic fibrosis. Thus leptin has been shown to induce TNF-α and IL-6 in the regenerative response to hepatic injury (12) and to promote HSC activation via hedgehog signaling (4). Accordingly, ob/ob mice in which fibrogenesis was induced with thioacetamide (TAA), carbon tetrachloride, or an MCD diet, displayed an attenuated hepatic profibrogenic TGF-β and procollagen type I mRNA expression, but these transcript levels were restored to increased levels after injection of leptin (11). Similarly, a leptin antagonist ameliorated TAA-induced liver fibrosis (6).However, hepatic fibrogenesis can be triggered and maintained by several chemokines and cytokines produced by immune and other cells, and does not solely rely on leptin signaling (18). In the present model, fibrogenesis could have been accelerated by a more excessive fat accumulation due to leptin deficiency and an unopposed generation of oxidative stress, which is considered a central driver of hepatocyte apoptosis and fatty liver inflammation (20). Notably, the present diet contained HTF, an important contributor to the development of hepatic steatosis and steatohepatitis (28), and high cholesterol (2%). The addition of 0.15–2% cholesterol to a steatogenic diet has previously been shown to exacerbate hepatic free cholesterol accumulation, which leads to severe steatosis, hepatocyte injury, macrophage recruitment, and liver fibrosis (3, 24, 27). Recently, Teratani et al. (27) provided a functional link between high dietary cholesterol and enhanced inflammation and fibrosis, demonstrating that in BL6 mice dietary cholesterol (1%) upregulated Toll-like receptor 4 on HSC, which suppressed the inhibitory TGF-β pseudorecepter Bambi, leading to increased TGF-β signaling, HSC activation, and fibrosis. Notably, the postulated mechanism was Kupffer cell- and leptin-independent. This may explain the development of fibrosis in leptin-deficient ob/ob mice by the HTF, high-fructose and high-cholesterol diet in the present paper. Taken together, reflecting the rare prevalence of leptin deficiency in man and the multiple and often divergent activities of leptin signaling in obesity and NASH, the relevance of ob/ob mice as preclinical model for human NASH is limited, and a model based on life style changes and metabolic alterations, such as a steatogenic, and, if possible, also fibrogenic diet is desirable.The model described by Trevaskis et al. (29) appears to come a step closer to such a humanized NASH model. However, a more rigorous fibrosis assessment would have been welcome, including hydoxyproline determination as a quantitative measure of collagen accumulation, picrosirius red staining for collagen, collagen morphometry on representative liver sections, and a broader quantitative PCR analysis of transcripts related to fibrogenesis, and fibrolysis, as well as more biochemical, histological, and transcript markers of lipid metabolism and inflammation (2, 17).Another novel aspect of the present paper is the effect of AC3174, a GLP-1 receptor (GLP-1R) agonist, in the novel NASH model applied to wild-type, ob/ob and GLP-1 receptor deficient (GLP-1RKO) mice. AC3174 is a peptide analogue of the GLP-1R agonist exenatide, with a leucine for methionine at position 14. GLP-1 lowers plasma glucose (9), mainly via its insulinotropic activity (29) coupled to improved insulin sensitivity (13). The GLP-1/GLP-1R system is complex and little studied in liver, and agonistic drugs may affect NAFL or NASH either by addressing the liver directly or indirectly (Fig. 1). AC3174 treatment significantly attenuated weight gain and especially the liver-to-body weight ratio, both in wild-type and ob/ob mice, but to a minor degree also in mice on a low-fat diet and in GLP-1RKO mice, indicating some unexplained off-target effect of this compound. This was accompanied by a significant though relatively modest effect on ALT and hepatic triglycerides. Collagen, as assessed by collagen Western blot analysis from liver extracts, a method that is unreliable, was highly significantly suppressed in AC3174-treated mice. The improvement of hepatic steatosis and presumably inflammation is likely due to activation of GLP-1R on hepatocytes, since others showed that exenatide stimulates hepatocyte expression of genes, such as PPAR-α and PPAR-γ, that improve hepatic fatty acid oxidation, lipid export, and insulin sensitivity (8, 25). Overall, the authors mainly used weight-based readouts in a limited number of animals, to assess the effect of AC3174 in fibrotic NASH, which requires confirmation, e.g., by use of a comparator drug, such as exenatide, and more on-target molecular biomarkers. Furthermore, the use of tissue (or cell)-specific conditional KO mice would provide more information on the utility of GLP-1R agonism in fatty liver disease. In addition to the already described beneficial aspects of exenatide on fibrogenesis (15, 26), GLP-1R agonists may also or predominantly modulate activated cholangiocytes (cells resembling hepatic progenitors) that are implicated in the progression of NASH as well as other liver diseases toward cirrhosis (16, 17, 19). Thus GLP-1 receptors are highly expressed on these cells, and GLP-1R activation blocks their Bax-induced mitochondrial apoptosis (15). Furthermore, GLP-1R agonists may protect the liver from apoptotic signals from hepatocytes, signals that can induce the production of hedgehog ligand, a mediator that can elicit and maintain HSC activation and fibrogenesis (26). Finally, GLP-1R is also found at nerve terminals in the portal vein, a site close to the origin of the major GLP-1 secretion site in the small intestine, and its inhibition was shown to promote insulin resistance (30).Fig. 1.Action of glucagon-like peptide-1 (GLP-1) and expression of GLP-1 receptors (GLP-1Rs). GLP-1 is induced postprandially and mainly secreted from intestinal L-cells and the neurons in the caudal regions of the nucleus of the solitary tract (NTS). The NTS then releases GLP-1 into the hypothalamus to control food intake. In the pancreas, activation of GLP-1R by intestinal GLP-1 stimulates insulin secretion, increases insulin sensitivity, and inhibits glucagon release. Elevated insulin combined with improved insulin signaling in glucoregulatory organs such as liver, adipose tissue, and muscle enhances glucose uptake and metabolism, which in turn reduces hepatic gluconeogenesis and improves steatosis. GLP-1 also dampens inflammatory immune responses, in part, by directly addressing immune cells, which finally ameliorates systemic (metabolic) inflammation and steatohepatitis. However, GLP-1 secreted by L-cells is rapidly inactivated by dipeptidyl peptidase-4 (DPP-4), which is ubiquitously expressed on most blood and tissue cells, underlining the utility of proteolytically stable GLP-1 mimetics or DPP-4 inhibitors to treat type 2 diabetes, the metabolic syndrome and likely nonalcoholic steatohepatitis (NASH). NAFLD, nonalcoholic fatty liver disease; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; RAGE, receptor of advanced glycation nd products; MCP-1, monocyte chemoattractant protein-1; PPAR, peroxisome proliferator-activated receptor; GLUT 2, glucose transporter 2; TLR-4, toll-like receptor-4, SOCS-3, suppressor of cytokine signaling-3; BDL, bile duct ligation; FAP, fibroblast activation protein; FFA, free fatty acids, eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase.Download figureDownload PowerPointOverall, the study by Trevaskis et al. (29) can be commended, since it addresses two topics that are highly relevant in current hepatological research: 1) a further improved dietary NASH model (addition of cholesterol to the diet); and 2) a novel therapeutic approach (GLP-1 agonism). However, some aspects need to be studied more in depth, e.g., using a more rigorous assessment of inflammation and fibrosis, preferably in wild-type mice, to assess the full potential of GLP-1 agonistic treatment in NAFLD, NASH, and the metabolic syndrome.GRANTSD. Schuppan receives funding from European Union, the State of Rhino-Palatinate, and the German Ministry of Education and Research.DISCLOSURESNo conflicts of interest are declared by the author(s).REFERENCES1. Anstee QM, Goldin RD. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Exp Pathol 87: 1–16, 2006.Crossref | PubMed | ISI | Google Scholar2. Hadi AM, Mouchaers KT, Schalij I, Grunberg K, Meijer GA, Vonk-Noordegraaf A, van der Laarse WJ, Beliën JA. Rapid quantification of myocardial fibrosis: a new macro-based automated analysis. Cell Oncol (Dordr) 34: 343–354, 2011.Crossref | PubMed | Google Scholar3. Charlton M, Krishnan A, Viker K, Sanderson S, Cazanave S, McConico A, Masuoko H, Gores G. Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. Am J Physiol Gastrointest Liver Physiol 301: G825–G834, 2011.Link | ISI | Google Scholar4. Choi SS, Syn WK, Karaca GF, Omenetti A, Moylan CA, Witek RP, Agboola KM, Jung Y, Michelotti GA, Diehl AM. Leptin promotes the myofibroblastic phenotype in hepatic stellate cells by activating the hedgehog pathway. J Biol Chem 285: 36551–36560, 2010.Crossref | PubMed | ISI | Google Scholar5. Dowman JK, Armstrong MJ, Tomlinson JW, Newsome PN. Current therapeutic strategies in non-alcoholic fatty liver disease. Diabetes Obes Metab 13: 692–702, 2011.Crossref | PubMed | ISI | Google Scholar6. Elinav E, Ali M, Bruck R, Brazowski E, Phillips A, Shapira Y, Katz M, Solomon G, Halpern Z, Gertler A. Competitive inhibition of leptin signaling results in amelioration of liver fibrosis through modulation of stellate cell function. Hepatology 49: 278–286, 2009.Crossref | PubMed | ISI | Google Scholar7. Fabbrini E, Magkos F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW, Okunade A, Klein S. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci USA 106: 15430–15435, 2009.Crossref | PubMed | ISI | Google Scholar8. Gupta NA, Mells J, Dunham RM, Grakoui A, Handy J, Saxena NK, Anania FA. Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology 51: 1584–1592, 2010.Crossref | PubMed | ISI | Google Scholar9. Hargrove DM, Kendall ES, Reynolds JM, Lwin AN, Herich JP, Smith PA, Gedulin BR, Flanagan SD, Jodka CM, Hoyt JA, McCowen KM, Parkes DG, Anderson CM. Biological activity of AC3174, a peptide analog of exendin-4. Regul Pept 141: 113–119, 2007.Crossref | PubMed | Google Scholar10. Honda H, Ikejima K, Hirose M, Yoshikawa M, Lang T, Enomoto N, Kitamura T, Takei Y, Sato N. Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver. Hepatology 36: 12–21, 2002.Crossref | PubMed | ISI | Google Scholar11. Leclercq IA, Farrell GC, Schriemer R, Robertson GR. Leptin is essential for the hepatic fibrogenic response to chronic liver injury. J Hepatol 37: 206–213, 2002.Crossref | PubMed | ISI | Google Scholar12. Leclercq IA, Field J, Farrell GC. Leptin-specific mechanisms for impaired liver regeneration in ob/ob mice after toxic injury. Gastroenterology 124: 1451–1464, 2003.Crossref | PubMed | ISI | Google Scholar13. Liu Q, Adams L, Broyde A, Fernandez R, Baron A, Parkes D. The exenatide analogue AC3174 attenuates hypertension, insulin resistance, and renal dysfunction in Dahl salt-sensitive rats. Cardiovasc Diabetol 9: 32, 2010.Crossref | PubMed | ISI | Google Scholar14. Lo L, McLennan SV, Williams PF, Bonner J, Chowdhury S, McCaughan GW, Gorrell MD, Yue DK, Twigg SM. Diabetes is a progression factor for hepatic fibrosis in a high fat fed mouse obesity model of non-alcoholic steatohepatitis. J Hepatol 55: 435–444, 2011.Crossref | PubMed | ISI | Google Scholar15. Marzioni M, Alpini G, Saccomanno S, Candelaresi C, Venter J, Rychlicki C, Fava G, Francis H, Trozzi L, Glaser S, Benedetti A. Glucagon-like peptide-1 and its receptor agonist exendin-4 modulate cholangiocyte adaptive response to cholestasis. Gastroenterology 133: 244–255, 2007.Crossref | PubMed | ISI | Google Scholar16. Patsenker E, Popov Y, Stickel F, Jonczyk A, Goodman SL, Schuppan D. Inhibition of integrin αvβ6 on cholangiocytes blocks transforming growth factor-β activation and retards biliary fibrosis progression. Gastroenterology 135: 660–670, 2008.Crossref | PubMed | ISI | Google Scholar17. Popov Y, Patsenker E, Stickel F, Zaks J, Bhaskar KR, Niedobitek G, Kolb A, Friess H, Schuppan D. Integrin αvβ6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies. J Hepatol 48: 453–464, 2008.Crossref | PubMed | ISI | Google Scholar18. Popov Y, Schuppan D. Targeting liver fibrosis: strategies for development and validation of antifibrotic therapies. Hepatology 50: 1294–1306, 2009.Crossref | PubMed | ISI | Google Scholar19. Richardson MM, Jonsson JR, Powell EE, Brunt EM, Neuschwander-Tetri BA, Bhathal PS, Dixon JB, Weltman MD, Tilg H, Moschen AR, Purdie DM, De metris AJ, Clouston AD. Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction. Gastroenterology 133: 80–90, 2007.Crossref | PubMed | ISI | Google Scholar20. Schattenberg M, Schuppan D. Nonalcoholic steatohepatitis: the therapeutic challenge of a global epidemic. Curr Opin Lipidol 22: 479–488, 2011.Crossref | PubMed | ISI | Google Scholar21. Schuppan D, Afdhal NH. Liver cirrhosis. Lancet 371: 838–851, 2008.Crossref | PubMed | ISI | Google Scholar22. Schuppan D, Gorrell MD, Klein T, Mark M, Afdhal NH. The challenge of developing novel pharmacological therapies for non-alcoholic steatohepatitis. Liver Int 30: 795–808, 2010.Crossref | PubMed | ISI | Google Scholar23. Sharma S, Mells JE, Fu PP, Saxena NK, Anania FA. GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS One 6: e25269, 2011.Crossref | PubMed | ISI | Google Scholar24. Subramanian S, Goodspeed L, Wang S, Kim J, Zeng L, Ioannou GN, Haigh WG, Yeh MM, Kowdley KV, O'Brien KD, Pennathur S, Chait A. Dietary cholesterol exacerbates hepatic steatosis and inflammation in obese LDL receptor-deficient mice. J Lipid Res 52: 1626–1635, 2011.Crossref | PubMed | ISI | Google Scholar25. Svegliati-Baroni G, Saccomanno S, Rychlicki C, Agostinelli L, De Minicis S, Candelaresi C, Faraci G, Pacetti D, Vivarelli M, Nicolini D, Garelli P, Casini A, Manco M, Mingrone G, Risaliti A, Frega GN, Benedetti A, Gastaldelli A. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int 31: 1285–1297, 2011.Crossref | PubMed | ISI | Google Scholar26. Syn WK, Choi SS, Liaskou E, Karaca GF, Agboola KM, Oo YH, Mi Z, Pereira TA, Zdanowicz M, Malladi P, Chen Y, Moylan C, Jung Y, Bhattacharya SD, Teaberry V, Omenetti A, Abdelmalek MF, Guy CD, Adams DH, Kuo PC, Michelotti GA, Whitington PF, Diehl AM. Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. Hepatology 53: 106–115, 2011.Crossref | PubMed | ISI | Google Scholar27. Teratani T, Tomita K, Suzuki T, Oshikawa T, Yokoyama H, Shimamura K, Tominaga S, Hiroi S, Irie R, Okada Y, Kurihara C, Ebinuma H, Saito H, Hokari R, Sugiyama K, Kanai T, Miura S, Hibi T. A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of free cholesterol in hepatic stellate cells. Gastroenterology 142: 152–164, 2012.Crossref | PubMed | ISI | Google Scholar28. Tetri LH, Basaranoglu M, Brunt EM, Yerian LM, Neuschwander-Tetri BA. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. Am J Physiol Gastrointest Liver Physiol 295: G987–G995, 2008.Link | ISI | Google Scholar29. 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. Am J Physiol Gastrointest Liver Physiol. doi:10.1152/ajpgi.00476.2011.Google Scholar30. Vahl TP, Tauchi M, Durler TS, Elfers EE, Fernandes TM, Bitner RD, Ellis KS, Woods SC, Seeley RJ, Herman JP, D'Alessio DA. Glucagon-like peptide-1 (GLP-1) receptors expressed on nerve terminals in the portal vein mediate the effects of endogenous GLP-1 on glucose tolerance in rats. Endocrinology 148: 4965–4973, 2007.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: D. Schuppan, Molecular and Translational Medicine, Dept. of Medicine I, Johannes Gutenberg Univ., Langenbeckstr. 1, 55131 Mainz, Germany (e-mail: detlef.[email protected]de). Download PDF Back to Top Next FiguresReferencesRelatedInformationCited ByProtective effect of alogliptin against cyclophosphamide-induced lung toxicity in rats: Impact on PI3K/Akt/FoxO1 pathway and downstream inflammatory cascades2 February 2022 | Cell and Tissue Research, Vol. 40Sitagliptin Is More Effective Than Gliclazide in Preventing Pro-Fibrotic and Pro-Inflammatory Changes in a Rodent Model of Diet-Induced Non-Alcoholic Fatty Liver Disease22 January 2022 | Molecules, Vol. 27, No. 3The role of bariatric surgery in the management of nonalcoholic steatohepatitis19 March 2021 | Current Opinion in Gastroenterology, Vol. 37, No. 3Influence of cardiometabolic comorbidities on myocardial function, infarction, and cardioprotection: Role of cardiac redox signalingFree Radical Biology and Medicine, Vol. 166Alterations in the Liver Fat Fraction Features Examined by Magnetic Resonance Imaging Following Bariatric Surgery: a Self-Controlled Observational Study11 February 2020 | Obesity Surgery, Vol. 30, No. 5The preventive effect of liraglutide on the lipotoxic liver injury via increasing autophagyAnnals of Hepatology, Vol. 19, No. 1The Role of GLP1 in Rat Steatotic and Non-Steatotic Liver Transplantation from Cardiocirculatory Death Donors9 December 2019 | Cells, Vol. 8, No. 12Liraglutide Inhibits Hepatitis C Virus Replication Through an AMP Activated Protein Kinase Dependent Mechanism14 September 2019 | International Journal of Molecular Sciences, Vol. 20, No. 18Continuous feeding of a combined high-fat and high-sucrose diet, rather than an individual high-fat or high-sucrose diet, rapidly enhances the glucagon-like peptide-1 secretory response to meal ingestion in diet-induced obese ratsNutrition, Vol. 62Resistant maltodextrin or fructooligosaccharides promotes GLP-1 production in male rats fed a high-fat and high-sucrose diet, and partially reduces energy intake and adiposity4 February 2017 | European Journal of Nutrition, Vol. 57, No. 3Secretion of GLP-1 but not GIP is potently stimulated by luminal d -Allulose ( d -Psicose) in ratsBiochemical and Biophysical Research Communications, Vol. 496, No. 3Gliptins Suppress Inflammatory Macrophage Activation to Mitigate Inflammation, Fibrosis, Oxidative Stress, and Vascular Dysfunction in Models of Nonalcoholic Steatohepatitis and Liver FibrosisAntioxidants & Redox Signaling, Vol. 28, No. 2GLP-1 Analogue, Exendin-4, Modulates MAPKs Activity but not the Heat Shock Response in Human HepG2 Cells28 November 2017 | PROTEOMICS - Clinical Applications, Vol. 12, No. 1Liraglutide attenuates partial warm ischemia-reperfusion injury in rat livers16 December 2016 | Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 390, No. 3Perspectives on Treatment for Nonalcoholic SteatohepatitisGastroenterology, Vol. 150, No. 8A computer model simulating human glucose absorption and metabolism in health and metabolic disease states12 April 2016 | F1000Research, Vol. 5Circulating dipeptidyl peptidase-4 activity correlates with measures of hepatocyte apoptosis and fibrosis in non-alcoholic fatty liver disease in type 2 diabetes mellitus and obesity: A dual cohort cross-sectional study22 December 2014 | Journal of Diabetes, Vol. 7, No. 6Identification of novel dipeptidyl peptidase 9 substrates by two-dimensional differential in-gel electrophoresis3 August 2015 | FEBS Journal, Vol. 282, No. 19DPP-IV inhibitor anagliptin exerts anti-inflammatory effects on macrophages, adipocytes, and mouse livers by suppressing NF-κB activationTakanori Shinjo, Yusuke Nakatsu, Misaki Iwashita, Tomomi Sano, Hideyuki Sakoda, Hisamitsu Ishihara, Akifumi Kushiyama, Midori Fujishiro, Toshiaki Fukushima, Yoshihiro Tsuchiya, Hideaki Kamata, Fusanori Nishimura, and Tomoichiro Asano1 August 2015 | American Journal of Physiology-Endocrinology and Metabolism, Vol. 309, No. 3Resistant maltodextrin promotes fasting glucagon-like peptide-1 secretion and production together with glucose tolerance in rats11 February 2015 | British Journal of Nutrition, Vol. 114, No. 1Rice protein hydrolysates stimulate GLP-1 secretion, reduce GLP-1 degradation, and lower the glycemic response in rats1 January 2015 | Food & Function, Vol. 6, No. 8The Glucagon-Like Peptide-1 Analogue Liraglutide Inhibits Oxidative Stress and Inflammatory Response in the Liver of Rats with Diet-Induced Non-alcoholic Fatty Liver DiseaseBiological & Pharmaceutical Bulletin, Vol. 38, No. 5Bariatric Surgery and Non-Alcoholic Fatty Liver Disease: Current and Potential Future Treatments27 October 2014 | Frontiers in Endocrinology, Vol. 5Quantitation of fibroblast activation protein (FAP)-specific protease activity in mouse, baboon and human fluids and organs8 December 2013 | FEBS Open Bio, Vol. 4, No. 1Pharmacological agents for nonalcoholic steatohepatitis19 November 2013 | Hepatology International, Vol. 7, No. S2Bariatric surgery for curing NASH in the morbidly obese?Journal of Hepatology, Vol. 58, No. 6 More from this issue > Video Abstract Volume 302Issue 8April 2012Pages G759-G761 Copyright & PermissionsCopyright © 2012 the American Physiological Societyhttps://doi.org/10.1152/ajpgi.00078.2012PubMed22383493History Published online 15 April 2012 Published in print 15 April 2012 Metrics