Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.
EBioMedicine. 2023 Jul;93:104684. doi: 10.1016/j.ebiom.2023.104684. Epub 2023 Jun 26.
Combined glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP1R) agonism is superior to single GLP1R agonism with respect to glycemic control and weight loss in obese patients with or without type 2 diabetes. As insulin resistance and obesity are strong risk factors for nonalcoholic fatty liver disease (NAFLD), in the current study we investigated the effects of combined GIPR/GLP1R agonism on NAFLD development.
Male APOE∗3-Leiden.CETP mice, a humanized model for diabetic dyslipidemia and NAFLD when fed a high-fat high-cholesterol diet, received subcutaneous injections with either vehicle, a GIPR agonist, a GLP1R agonist, or both agonists combined every other day.
GIPR and GLP1R agonism reduced body weight and additively lowered fasting plasma levels of glucose, triglycerides and total cholesterol. Strikingly, we report an additive reduction in hepatic steatosis as evidenced by lower hepatic lipid content and NAFLD scores. Underlying the lipid-lowering effects were a reduced food intake and intestinal lipid absorption and an increased uptake of glucose and triglyceride-derived fatty acids by energy-combusting brown adipose tissue. Combined GIPR/GLP1R agonism also attenuated hepatic inflammation as evidenced by a decreased number of monocyte-derived Kupffer cells and a reduced expression of inflammatory markers. Together, the reduced hepatic steatosis and inflammation coincided with lowered markers of liver injury.
We interpretate that GIPR and GLP1R agonism additively attenuate hepatic steatosis, lower hepatic inflammation, ameliorate liver injury, together preventing NAFLD development in humanized APOE∗3-Leiden.CETP mice. We anticipate that combined GIPR/GLP1R agonism is a promising strategy to attenuate NAFLD progression in humans.
This work was supported by a grant from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences [CVON-GENIUS-II] to P.C.N.R., a Lilly Research Award Program [LRAP] Award to P.C.N.R. and S.K., a Dutch Heart Foundation [2017T016] grant to S.K., and an NWO-VENI grant [09150161910073] to M.R.B.; J.F.D.B. is supported by the Nutrition and Health initiative of the University of Groningen; Z.Y. is supported by a full-time PhD scholarship from the China Scholarship Council (201806850094 to Z.Y.).
在肥胖伴或不伴 2 型糖尿病的患者中，与单独的 GLP1R 激动剂相比，联合应用葡萄糖依赖性胰岛素促分泌多肽受体（GIPR）和胰高血糖素样肽-1 受体（GLP1R）激动剂在血糖控制和体重减轻方面更具优势。由于胰岛素抵抗和肥胖是非酒精性脂肪性肝病（NAFLD）的强烈危险因素，在目前的研究中，我们研究了联合应用 GIPR/GLP1R 激动剂对 NAFLD 发展的影响。
载脂蛋白 E3-Leiden.CETP 雄性小鼠是一种模拟糖尿病血脂异常和非酒精性脂肪性肝病的人源化模型，当给予高脂肪高胆固醇饮食时，每隔一天接受皮下注射载体、GIPR 激动剂、GLP1R 激动剂或两者联合应用。
GIPR 和 GLP1R 激动剂可降低体重，并可附加降低空腹血糖、甘油三酯和总胆固醇水平。值得注意的是，我们报告了肝脂肪变性的附加减少，表现为肝脂质含量和非酒精性脂肪性肝病评分降低。降低脂质的作用是通过减少食物摄入和肠道脂质吸收以及增加棕色脂肪组织消耗的葡萄糖和甘油三酯衍生脂肪酸的摄取来实现的。联合应用 GIPR/GLP1R 激动剂还可减轻肝炎症，表现为单核细胞衍生的枯否细胞数量减少和炎症标志物表达降低。总的来说，肝脂肪变性和炎症的减少与肝损伤标志物的降低相吻合。
我们认为 GIPR 和 GLP1R 激动剂可附加减轻肝脂肪变性，降低肝炎症，改善肝损伤，共同预防载脂蛋白 E3-Leiden.CETP 小鼠的非酒精性脂肪性肝病的发生。我们预计联合应用 GIPR/GLP1R 激动剂是一种有前途的策略，可以减轻人类非酒精性脂肪性肝病的进展。
本工作得到荷兰心血管研究倡议的资助：荷兰心脏基金会、荷兰大学医学中心联合会、荷兰健康研究与发展组织和荷兰皇家科学院[CVON-GENIUS-II]资助 P.C.N.R.，礼来研究奖计划[LRAP]资助 P.C.N.R.和 S.K.，荷兰心脏基金会[2017T016]资助 S.K.，NWO-VENI 资助[09150161910073]资助 M.R.B.；J.F.D.B.得到格罗宁根大学营养与健康倡议的支持；Z.Y.得到中国国家留学基金委全额博士奖学金（201806850094 至 Z.Y.）的支持。
