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.
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DOI：
10.1016/j.molmet.2017.07.016
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发表时间：
2017-10
影响因子：
8.1
通讯作者：
Schürmann A
中科院分区：
文献类型：
--
作者：
Baumeier C;Schlüter L;Saussenthaler S;Laeger T;Rödiger M;Alaze SA;Fritsche L;Häring HU;Stefan N;Fritsche A;Schwenk RW;Schürmann A
二肽基肽酶4 （DPP4）的肝脏表达增加与非酒精性脂肪性肝病（NAFLD）有关。这是否是NAFLD发生的原因尚不清楚。在此，我们研究了肝脏DPP4过表达对饮食性肥胖小鼠肝脏脂肪变性的影响。分析NAFLD患者和非NAFLD患者血浆DPP4活性。野生型（WT）和肝脏特异性Dpp4转基因小鼠（Dpp4- liv - tg）饲喂高脂肪饲料，测定体重、体成分、肝脏脂肪含量和胰岛素敏感性。通过HepG2细胞和小鼠原代肝细胞的体外实验，验证DPP4对脂质储存和胰岛素敏感性的细胞自主作用。与健康对照相比，患有胰岛素抵抗和NAFLD的受试者血浆DPP4活性增加。DPP4 - liv - tg小鼠的分析显示，全身DPP4活性升高，GLP-1活性降低。此外，他们还表现出体重增加、脂肪量增加、脂肪组织炎症、肝脂肪变性、肝损伤和高胆固醇血症。这些影响伴随着肝脏中PPARγ和CD36表达的增加以及严重的胰岛素抵抗。与此一致的是，用生理浓度的DPP4治疗HepG2细胞和原代肝细胞会导致胰岛素敏感性受损，而不依赖于脂质含量。我们的研究结果表明，肝脏中DPP4的表达升高可促进NAFLD和胰岛素抵抗。这与GLP-1活性水平降低有关，但也与DPP4对肝脏胰岛素信号的自动和旁分泌作用有关。NAFLD患者血浆DPP4活性增强。促进脂肪肝疾病。诱导肝脏胰岛素抵抗。降低全身GLP-1活性水平促进脂肪组织扩张和炎症。小鼠肝细胞特异性DPP4过表达。
Increased 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. Plasma 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. Subjects 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. Our 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. NAFLD patients have augmented plasma DPP4 activity. promotes fatty liver disease. induces hepatic insulin resistance. reduces systemic levels of active GLP-1. enhances adipose tissue expansion and inflammation. Hepatocyte-specific DPP4 overexpression in mice.
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影响因子：
3.7
作者：
Firneisz G;Varga T;Lengyel G;Fehér J;Ghyczy D;Wichmann B;Selmeci L;Tulassay Z;Rácz K;Somogyi A
通讯作者：
Somogyi A
DOI：
10.1016/j.bbalip.2015.01.013
发表时间：
2015-05-01
影响因子：
4.8
作者：
Baumeier, Christian;Kaiser, Daniel;Schuermann, Annette
通讯作者：
Schuermann, Annette
影响因子：
3.8
作者：
Balaban, Yasemin H.;Korkusuz, Petek;Tatar, Gonca
通讯作者：
Tatar, Gonca
影响因子：
7.7
作者：
Baumeier, Christian;Saussenthaler, Sophie;Schwenk, Robert W.
通讯作者：
Schwenk, Robert W.
影响因子：
3.7
作者：
Lubura M;Hesse D;Neumann N;Scherneck S;Wiedmer P;Schürmann A
通讯作者：
Schürmann A