Prevention and treatment effect of evogliptin on hepatic steatosis in high-fat-fed animal models

Kim, Mi-Kyung; Chae, Yu Na; Ahn, Gook-Jun; Shin, Chang Yell; Choi, Song-hyen; Yang, Eun Kyoung; Sohn, Yong Sung; Son, Moon-Ho

doi:10.1007/s12272-016-0864-z

Cited by 23 publications

(26 citation statements)

References 47 publications

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“…Furthermore, studies in primary human adipocytes showed insulin resistance by the administration of recombinant DPP4 [18] and improved insulin sensitivity when DPP4 was downregulated [20] . Moreover, long-term DPP4 inhibition improved insulin sensitivity and reduced liver fat content in animals with diet-induced hepatic steatosis and insulin resistance [16] , [33] . Thus, DPP4 has an autocrine effect on hepatic insulin signaling which might contribute to later accumulation of ectopic fat in the liver.…”

Section: Discussionmentioning

confidence: 99%

Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver disease

Baumeier

Schlüter

Saussenthaler

et al. 2017

Molecular Metabolism

121

106

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ObjectiveIncreased hepatic expression of dipeptidyl peptidase 4 (DPP4) is associated with non-alcoholic fatty liver disease (NAFLD). Whether this is causative for the development of NAFLD is not yet clarified. Here we investigate the effect of hepatic DPP4 overexpression on the development of liver steatosis in a mouse model of diet-induced obesity.MethodsPlasma DPP4 activity of subjects with or without NAFLD was analyzed. Wild-type (WT) and liver-specific Dpp4 transgenic mice (Dpp4-Liv-Tg) were fed a high-fat diet and characterized for body weight, body composition, hepatic fat content and insulin sensitivity. In vitro experiments on HepG2 cells and primary mouse hepatocytes were conducted to validate cell autonomous effects of DPP4 on lipid storage and insulin sensitivity.ResultsSubjects suffering from insulin resistance and NAFLD show an increased plasma DPP4 activity when compared to healthy controls. Analysis of Dpp4-Liv-Tg mice revealed elevated systemic DPP4 activity and diminished active GLP-1 levels. They furthermore show increased body weight, fat mass, adipose tissue inflammation, hepatic steatosis, liver damage and hypercholesterolemia. These effects were accompanied by increased expression of PPARγ and CD36 as well as severe insulin resistance in the liver. In agreement, treatment of HepG2 cells and primary hepatocytes with physiological concentrations of DPP4 resulted in impaired insulin sensitivity independent of lipid content.ConclusionsOur results give evidence that elevated expression of DPP4 in the liver promotes NAFLD and insulin resistance. This is linked to reduced levels of active GLP-1, but also to auto- and paracrine effects of DPP4 on hepatic insulin signaling.

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Section: Discussionmentioning

confidence: 99%

Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver disease

Baumeier

Schlüter

Saussenthaler

et al. 2017

Molecular Metabolism

121

106

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“…NAFLD is a chronic inflammatory disorder associated with increased hepatic expression of DPP-4; therefore, inhibition of DPP-4 could ameliorate NAFLD [ 16 ]. DPP-4 inhibitors have been reported to decrease lipid accumulation in HFD-induced hepatic steatosis [ 10 , 11 , 12 , 13 , 14 , 17 ]. However, few studies have examined the mechanism underlying the beneficial effects of DPP-4 inhibitors on NAFLD [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…Evogliptin (Evo), a novel DPP-4 inhibitor, was recently approved for type 2 diabetes by the South Korean Ministry of Food and Drug Safety. It has been found to prevent hepatic steatosis in animal models by suppression of de novo lipogenesis [ 14 ]. However, the precise underlying mechanisms are unclear.…”

Section: Introductionmentioning

confidence: 99%

Protective Effects of Evogliptin on Steatohepatitis in High-Fat-Fed Mice

Kim

Jang

Roh

et al. 2020

IJMS

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There are few studies on the effects of dipeptidyl peptidase-4 inhibitors on steatohepatitis. We explored whether evogliptin (Evo), a dipeptidyl peptidase-4 inhibitor, protects against steatohepatitis in a high-fat diet (HFD)-fed mice and whether these effects involve modulation of mitophagy. Adult male C57BL/J mice were divided into the normal diet (ND), HFD (45% of energy from fat) with Evo (250 mg/kg) (HFD + Evo), and HFD groups at 4 weeks of age and were sacrificed at 20 weeks of age. The HFD group showed hepatic lipid accumulation; this was decreased in the Evo + HFD group. There was an increased 8-hydroxydeoxyguanosine (8-OHDG) expression in the HFD group compared to ND mice. However, 8-OHDG expression levels were significantly decreased in the HFD + Evo group. Expressions of the mitophagy markers PTEN-induced kinase 1 (PINK1), Parkin, and BNIP-3 (BCL2 Interacting Protein 3) were significantly increased in the HFD group. However, the expressions of these markers were lower in the HFD + Evo group than that in the HFD group. Phospho-Akt was upregulated and p53 was downregulated in the HFD + Evo group compared to the HFD group. Evogliptin may alleviate steatohepatitis in HFD-fed mice by ameliorating steatosis and oxidative stress and by modulating mitophagy in the liver.

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“…142 They primarily lower the postprandial glucose level, as they inhibit the plasma degrading enzyme DPP-IV, leading to higher plasma GLP-1 levels. 98 There is a good rationale for their use to treat NAFLD as many studies in vitro 143 and in animal models of NAFLD/NASH [144][145][146][147][148][149][150][151][152][153][154] have reported marked beneficial effects.…”

Section: Lactate Amino Acidsmentioning

confidence: 99%

From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options

2019

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The worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) is estimated to have reached 25% or more in adults. NAFLD is prevalent in obese individuals, but may also affect nonobese insulin-resistant individuals. NAFLD is associated with a 2-to 3-fold increased risk of developing type 2 diabetes (T2D), which may be higher in patients with more severe liver diseasefibrosis increases this risk. In NAFLD, not only the close association with obesity, but also the impairment of many metabolic pathways, including decreased hepatic insulin sensitivity and insulin secretion, increase the risk of developing T2D and related comorbidities. Conversely, patients with diabetes have a higher prevalence of steatohepatitis, liver fibrosis and end-stage liver disease. Genetics and mechanisms involving dysfunctional adipose tissue, lipotoxicity and glucotoxicity appear to play a role. In this review, we discuss the altered pathophysiological mechanisms that underlie the development of T2D in NAFLD and vice versa. Although there is no approved therapy for the treatment of NASH, we discuss pharmacological agents currently available to treat T2D that could potentially be useful for the management of NASH.

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Prevention and treatment effect of evogliptin on hepatic steatosis in high-fat-fed animal models

Cited by 23 publications

References 47 publications

Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver disease

Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver disease

Protective Effects of Evogliptin on Steatohepatitis in High-Fat-Fed Mice

From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options

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