Dipeptidyl peptidase-4 inhibition ameliorates Western diet-induced hepatic steatosis and insulin resistance through hepatic lipid remodeling and modulation of hepatic mitochondrial function.
Dipeptidyl peptidase-4 inhibition ameliorates Western diet-induced hepatic steatosis and insulin resistance through hepatic lipid remodeling and modulation of hepatic mitochondrial function.
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作者：
Aroor AR;Habibi J;Ford DA;Nistala R;Lastra G;Manrique C;Dunham MM;Ford KD;Thyfault JP;Parks EJ;Sowers JR;Rector RS
西方人群中肝脂肪变性的患病率日益增加，需要新的治疗方法。在这方面，二肽基肽酶 - 4（DPP - 4）抑制剂最近被报道可减轻肝脂肪变性的发展，但其潜在机制仍不明确。在当前的研究中，4周龄的C57Bl / 6小鼠被喂食高脂/高果糖的西方饮食（WD）或含有DPP - 4抑制剂MK0626的西方饮食，持续16周。DPP - 4抑制剂通过增强胰岛素对肝脏葡萄糖输出的抑制作用，防止了西方饮食诱导的肝脂肪变性，并降低了肝脏胰岛素抵抗。西方饮食诱导的肝脏三酰甘油（TAG）和二酰甘油（DAG）含量的积累在DPP - 4抑制剂治疗下显著减少。此外，MK0626显著减少了线粒体棕榈酸不完全氧化，并增加了丙酮酸脱氢酶活性、三羧酸循环通量和肝脏TAG分泌的指标。进一步地，DPP - 4抑制挽救了西方饮食诱导的肝脏PGC - 1α和CPT - 1 mRNA表达以及肝脏Sirt1蛋白含量的下降。而且，MK0626治疗后，喂食西方饮食的小鼠血浆尿酸水平降低。这些研究表明，DPP - 4抑制通过增强线粒体碳水化合物利用和肝脏TAG分泌/输出，同时减少尿酸生成，抑制肝脏TAG和DAG积累，从而改善肝脂肪变性和胰岛素抵抗。
Novel therapies are needed for treating the increasing prevalence of hepatic steatosis in Western populations. In this regard, dipeptidyl peptidase-4 (DPP-4) inhibitors have recently been reported to attenuate the development of hepatic steatosis, but the potential mechanisms remain poorly defined. In the current study, 4-week-old C57Bl/6 mice were fed a high-fat/high-fructose Western diet (WD) or a WD containing the DPP-4 inhibitor, MK0626, for 16 weeks. The DPP-4 inhibitor prevented WD-induced hepatic steatosis and reduced hepatic insulin resistance by enhancing insulin suppression of hepatic glucose output. WD-induced accumulation of hepatic triacylglycerol (TAG) and diacylglycerol (DAG) content was significantly attenuated with DPP-4 inhibitor treatment. In addition, MK0626 significantly reduced mitochondrial incomplete palmitate oxidation and increased indices of pyruvate dehydrogenase activity, TCA cycle flux, and hepatic TAG secretion. Furthermore, DPP-4 inhibition rescued WD-induced decreases in hepatic PGC-1α and CPT-1 mRNA expression and hepatic Sirt1 protein content. Moreover, plasma uric acid levels in mice fed the WD were decreased after MK0626 treatment. These studies suggest that DPP-4 inhibition ameliorates hepatic steatosis and insulin resistance by suppressing hepatic TAG and DAG accumulation through enhanced mitochondrial carbohydrate utilization and hepatic TAG secretion/export with a concomitant reduction of uric acid production.
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影响因子：
120.7
作者：
Flegal, Katherine M.;Carroll, Margaret D.;Curtin, Lester R.
通讯作者：
Curtin, Lester R.
在四种常用的近交小鼠菌株中的体内葡萄糖代谢。
影响因子：
7.7
作者：
Berglund, Eric D.;Li, Candice Y.;Poffenberger, Greg;Ayala, Julio E.;Fueger, Patrick T.;Willis, Shannon E.;Jewell, Marybeth M.;Powers, Alvin C.;Wasserman, David H.
通讯作者：
Wasserman, David H.
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
影响因子：
29
作者：
Farese RV Jr;Zechner R;Newgard CB;Walther TC
通讯作者：
Walther TC
影响因子：
13.5
作者：
Ishimoto, Takuji;Lanaspa, Miguel A.;Rivard, Christopher J.;Roncal-Jimenez, Carlos A.;Orlicky, David J.;Cicerchi, Christina;McMahan, Rachel H.;Abdelmalek, Manal F.;Rosen, Hugo R.;Jackman, Matthew R.;MacLean, Paul S.;Diggle, Christine P.;Asipu, Aruna;Inaba, Shinichiro;Kosugi, Tomoki;Sato, Waichi;Maruyama, Shoichi;Sanchez-Lozada, Laura G.;Sautin, Yuri Y.;Hill, James O.;Bonthron, David T.;Johnson, Richard J.
通讯作者：
Johnson, Richard J.