Decreased Hyocholic Acid and Lysophosphatidylcholine Induce Elevated Blood Glucose in a Transgenic Porcine Model of Metabolic Disease

文献类型： 外文期刊

第一作者： Xu, Jianping

作者： Xu, Jianping;Liu, Xiaoyu;Xiao, Xinhua;Zhang, Kaiyi;Yang, Shulin;Zhang, Kaiyi;Qiu, Bintao;Liu, Jieying

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关键词： high-fat high-sucrose diet; metabolic diseases; pig model; metabolome; lipidome

期刊名称：METABOLITES （ 影响因子：5.581； 五年影响因子：5.531 ）

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年卷期： 2022 年 12 卷 12 期

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收录情况： SCI

摘要： (1) Background: This work aims to investigate the metabolomic changes in PIGinH11 pigs and investigate differential compounds as potential therapeutic targets for metabolic diseases. (2) Methods: PIGinH11 pigs were established with a CRISPR/Cas9 system. PNPLA3(I148M), hIAPP, and GIPR(dn) were knocked in the H11 locus of the pig genome. The differential metabolites between and within groups were compared at baseline and two months after high-fat-high-sucrose diet induction. (3) Results: 72.02% of the 815 detected metabolites were affected by the transgenic effect. Significantly increased metabolites included isoleucine, tyrosine, methionine, oxoglutaric acid, acylcarnitine, glucose, sphinganines, ceramides, and phosphatidylserines, while fatty acids and conjugates, phosphatidylcholines, phosphatidylethanolamines, and sphingomyelins were decreased. Lower expression of GPAT3 and higher expression of PNPLA3(I148M) decreased the synthesis of diacylglycerol and phosphatidylcholines. Accumulated ceramides that block Akt signaling and decrease hyocholic acid and lysophosphatidylcholines might be the main reason for increased blood glucose in PIGinH11 pigs, which was consistent with metabolomic changes in patients. (4) Conclusions: Through serum metabolomics and lipidomics studies, significant changes in obesity and diabetes-related biomarkers were detected in PIGinH11 pigs. Excessive fatty acids beta-oxidation interfered with glucose and amino acids catabolism and reduced phosphatidylcholines. Decreased hyocholic acid, lysophosphatidylcholine, and increased ceramides exacerbated insulin resistance and elevated blood glucose. Phosphatidylserines were also increased, which might promote chronic inflammation by activating macrophages.

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