Dipeptidyl Peptidase 4-Deficient Rats Have Improved Bile Secretory Function in High Fat Diet-Induced Steatosis

Shlomo, Shani Ben; Zvibel, Isabel; Rabinowich, Liane; Goldiner, Ilana; Shlomai, Amir; Santo, Erwin; Halpern, Zamir; Oren, Ran; Fishman, Sigal

doi:10.1007/s10620-012-2353-7

Cited by 12 publications

(16 citation statements)

References 19 publications

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“…Normal and high fat diet fed DPP4-deficient rats exhibited reduced hepatic triglycerides, accompanied by the down-regulation of lipogenesis enzymes and the parallel up-regulation of carnitine palmitoyltransferase-1, a key enzyme in fatty acid β-oxidation[30]. Rats with DPP4 deficiency have improved bile secretory function in a high fat diet-induced steatosis model[7]. In patients with T2D and/or morbid obesity, circulating DPP4 activity is associated with current apoptosis and liver fibrosis[31].…”

Section: Discussionmentioning

confidence: 99%

Linagliptin alleviates fatty liver disease in diabetic db/db mice

Мичурина¹,

Ishenko²,

Климонтов³

et al. 2016

WJD

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AIMTo study the effects of linagliptin on the structural signs of non-alcoholic fatty liver disease (NAFLD) in db/db mice.METHODSMale diabetic db/db mice (BKS.Cg-Dock7m+/+Leprdb/J) aged 10 wk received the dipeptidyl peptidase 4 (DPP4) inhibitor linagliptin (10 mg/kg) or saline as a placebo once per day by gavage for 8 wk. Intact db/db mice served as controls. Structural changes in the liver were analyzed from light and electron microscopic images of sections from intact, placebo-treated and linagliptin-treated animals. We estimated the changes in hepatocytes, sinusoidal cells, liver microvasculature and lymphatic roots. Hepatic staining for lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) was assessed by immunohistochemistry.RESULTSIn 18-wk-old diabetic mice, liver steatosis (predominantly microvesicular and mediovesicular steatosis) was accompanied by dilation of the roots of the lymphatic system, interlobular blood vessels and bile canaliculi. Compared to saline-treated mice, linagliptin-treated mice exhibited a reduction in the mean numeral densities of hepatocytes with lipid droplets (92.4% ± 1.7% vs 64.9% ± 5.8% per field of view, P = 0.0002) and a lower proportion of hepatocytes with a high density of lipid droplets (20.7% ± 3.6% vs 50.4% ± 3.1%, P = 0.0007). We observed heterogeneous hepatocytes and relatively preserved cell structures in the linagliptin group. Dilation of blood and lymphatic vessels, as well as ultrastructural changes in the hepatocyte endoplasmic reticulum and mitochondria, were alleviated by linagliptin treatment. In intact and placebo-treated mice, immunohistochemical staining for LYVE-1 was observed in the endothelial cells of interlobular lymphatic vessels and on the membranes of some endothelial sinusoidal cells. We observed an enlarged LYVE-1 reaction area in linagliptin-treated mice compared to intact and placebo-treated mice. The improvement in the structural parameters of the liver in linagliptin-treated mice was independent to changes in the plasma glucose levels.CONCLUSIONThe DPP4 inhibitor linagliptin alleviates liver steatosis and structural changes in the hepatic microvasculature and lymphatic roots in a model of NAFLD in diabetic db/db mice.

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Section: Discussionmentioning

confidence: 99%

Linagliptin alleviates fatty liver disease in diabetic db/db mice

Мичурина¹,

Ishenko²,

Климонтов³

et al. 2016

WJD

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“…Treatment of diabetic rodents with DPP4 inhibitors reduces hepatic steatosis and fibrosis and decreases hepatic inflammation; however, the underlying mechanisms have not been identified (214). Similarly, high-fat-fed F344/DuCrj DPP4 rats exhibited a reduction in both plasma and hepatic triglyceride and lower levels of molecular markers of proinflammatory and profibrotic cytokines including IL-6, TNF␣, plasminogen activator inhibitor-1, connective tissue growth factor and TGF␤ (215). Although the authors postulate that these actions were mediated through potentiation of direct GLP-1 actions on hepatocytes, it seems unlikely that hepatocytes express the canonical GLP-1R (216).…”

Section: Livermentioning

confidence: 99%

Pharmacology, Physiology, and Mechanisms of Action of Dipeptidyl Peptidase-4 Inhibitors

2014

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Dipeptidyl peptidase-4 (DPP4) is a widely expressed enzyme transducing actions through an anchored transmembrane molecule and a soluble circulating protein. Both membrane-associated and soluble DPP4 exert catalytic activity, cleaving proteins containing a position 2 alanine or proline. DPP4-mediated enzymatic cleavage alternatively inactivates peptides or generates new bioactive moieties that may exert competing or novel activities. The widespread use of selective DPP4 inhibitors for the treatment of type 2 diabetes has heightened interest in the molecular mechanisms through which DPP4 inhibitors exert their pleiotropic actions. Here we review the biology of DPP4 with a focus on: 1) identification of pharmacological vs physiological DPP4 substrates; and 2) elucidation of mechanisms of actions of DPP4 in studies employing genetic elimination or chemical reduction of DPP4 activity. We review data identifying the roles of key DPP4 substrates in transducing the glucoregulatory, anti-inflammatory, and cardiometabolic actions of DPP4 inhibitors in both preclinical and clinical studies. Finally, we highlight experimental pitfalls and technical challenges encountered in studies designed to understand the mechanisms of action and downstream targets activated by inhibition of DPP4.

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“…In addition, GLP-1 influences bile metabolism 87. It lowers bile acid production and increases excretion, thereby lowering the bile acid exposure of hepatocytes 146. In vitro, GLP-1 and the GLP-1RA exendin-4 increase cholangiocyte proliferation and reduce apoptosis 147.…”

Section: Gi Effects Of Glp-1 Based Therapiesmentioning

confidence: 99%

GLP-1 based therapies: clinical implications for gastroenterologists

Smits

Raalte

Tonneijck

et al. 2016

Gut

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The gut-derived incretin hormone, glucagon-like peptide 1 (GLP-1) lowers postprandial blood glucose levels by stimulating insulin and inhibiting glucagon secretion. Two novel antihyperglycaemic drug classes augment these effects; GLP-1 receptor agonists and inhibitors of the GLP-1 degrading enzyme dipeptidyl peptidase 4. These so called GLP-1 based or incretin based drugs are increasingly used to treat type 2 diabetes, because of a low risk of hypoglycaemia and favourable effect on body weight, blood pressure and lipid profiles. Besides glucose control, GLP-1 functions as an enterogastrone, causing a wide range of GI responses. Studies have shown that endogenous GLP-1 and its derived therapies slow down digestion by affecting the stomach, intestines, exocrine pancreas, gallbladder and liver. Understanding the GI actions of GLP-1 based therapies is clinically relevant; because GI side effects are common and need to be recognised, and because these drugs may be used to treat GI disease.

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Dipeptidyl Peptidase 4-Deficient Rats Have Improved Bile Secretory Function in High Fat Diet-Induced Steatosis

Abstract: Our data suggest that GLP-1 analogs may serve as a novel therapeutic drug to alleviate obesity-induced liver injury by reducing bile acid synthesis and improving liver bile secretory function.

Cited by 12 publications

References 19 publications

Linagliptin alleviates fatty liver disease in diabetic db/db mice

Linagliptin alleviates fatty liver disease in diabetic db/db mice

Pharmacology, Physiology, and Mechanisms of Action of Dipeptidyl Peptidase-4 Inhibitors

GLP-1 based therapies: clinical implications for gastroenterologists

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