[en] (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. PNPLA3I148M, hIAPP, and GIPRdn 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 PNPLA3I148M 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 β-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.
Xu, Jianping ✱; The Ministry of Health Key Laboratory of Endocrinology, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
Zhang, Kaiyi ✱; Université de Liège - ULiège > TERRA Research Centre ; State Key Laboratory of Animal Nutrition, Ministry of Agriculture Key Laboratory of Animal Genetics Breeding and Reproduction, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
Qiu, Bintao; The Ministry of Health Key Laboratory of Endocrinology, Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
Liu, Jieying; The Ministry of Health Key Laboratory of Endocrinology, Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
Liu, Xiaoyu; The Ministry of Health Key Laboratory of Endocrinology, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
Yang, Shulin; State Key Laboratory of Animal Nutrition, Ministry of Agriculture Key Laboratory of Animal Genetics Breeding and Reproduction, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
Xiao, Xinhua; The Ministry of Health Key Laboratory of Endocrinology, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
✱ These authors have contributed equally to this work.
Language :
English
Title :
Decreased Hyocholic Acid and Lysophosphatidylcholine Induce Elevated Blood Glucose in a Transgenic Porcine Model of Metabolic Disease.
NSCF - National Natural Science Foundation of China
Funding text :
This research was funded by the National Natural Science Foundation of China, grant number 32070535 and 81770832; the National Key R&D Program of China, grant number 2021YFA0805903; the State Key Laboratory of Animal Nutrition, grant number 2004DA125184F1913; and the Agricultural Science and Technology Innovation Program, grant number ASTIP-IAS05 and ASTIP-IAS-TS-4.
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