Maternal high-fat diet regulates offspring hepatic ABCG5 expression and cholesterol metabolism via the gut microbiota and its derived butyrate.

IF 6.7 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Clinical science Pub Date : 2024-09-04 DOI:10.1042/CS20240997
Ling Zhang, Shixuan Zhang, Wenyu Zou, Yongyan Hu, Ying Gao, Junqing Zhang, Jia Zheng
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Abstract

Maternal high-fat diet intake has profound effects on the long-term health of offspring, predisposing them to a higher susceptibility to obesity and metabolic dysfunction-associated steatotic liver disease. However, the detailed mechanisms underlying the role of a maternal high-fat diet in hepatic lipid accumulation in offspring, especially at the weaning age, remain largely unclear. In this study, female C57BL/6J mice were randomly assigned to either a high-fat diet or a control diet, and lipid metabolism parameters were assessed in male offspring at weaning. Gut microbiota analysis and targeted metabolomics of short-chain fatty acids (SCFAs) in these offspring were further performed. Both in vivo and in vitro studies were conducted to explore the role of butyrate in hepatic cholesterol excretion in the liver and HepG2 cells. Our results showed that maternal high-fat feeding led to obesity and dyslipidemia, and exacerbated hepatic lipid accumulation in the livers of offspring at weaning. We observed significant decreases in the abundance of the Firmicutes phylum and the Allobaculum genus, known as producers of SCFAs, particularly butyrate, in the offspring of dams fed a high-fat diet. Additionally, maternal high-fat diet feeding markedly decreased serum butyrate levels and down-regulated ATP-binding cassette transporters G5 (ABCG5) in the liver, accompanied by decreased phosphorylated AMP-activated protein kinase (AMPK) and histone deacetylase 5 (HADC5) expressions. Subsequent in vitro studies revealed that butyrate could induce ABCG5 activation and alleviate lipid accumulation via the AMPK-pHDAC5 pathway in HepG2 cells. Moreover, knockdown of HDAC5 up-regulated ABCG5 expression and promoted cholesterol excretion in HepG2 cells. In conclusion, our study provides novel insights into how maternal high-fat diet feeding inhibits hepatic cholesterol excretion and down-regulates ABCG5 through the butyrate-AMPK-pHDAC5 pathway in offspring at weaning.

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母体高脂肪饮食通过肠道微生物群及其衍生的丁酸盐调节后代肝脏 ABCG5 的表达和胆固醇代谢。
母体摄入高脂肪饮食会对后代的长期健康产生深远影响,使其易患代谢功能障碍相关的脂肪肝。然而,其具体机制在很大程度上仍不清楚。在这项研究中,雌性 C57BL/6J 小鼠被随机分配到高脂饮食或对照饮食中,断奶时对雄性后代的脂代谢参数进行了评估。研究还进一步对这些后代进行了肠道微生物群分析和短链脂肪酸(SCFA)靶向代谢组学研究。我们还进行了体内和体外研究,以探讨丁酸盐在肝脏和 HepG2 细胞中肝胆固醇排泄中的作用。我们的研究结果表明,母体高脂肪喂养会导致肥胖和血脂异常,并加剧断奶后代肝脏中的肝脂积累。我们观察到,在高脂肪母体的后代中,固醇菌门和Allobaculum属(众所周知,它们是SCFAs(尤其是丁酸盐)的生产者)的丰度下降。此外,母体摄入高脂饮食会显著降低血清中的丁酸盐含量,并下调肝脏中的 ATP 结合盒转运体 G5(ABCG5),同时降低磷酸化 AMP 激活蛋白激酶(AMPK)和组蛋白去乙酰化酶 5(HADC5)的表达。随后的体外研究发现,丁酸盐可诱导 ABCG5 活化,并通过 AMPK-pHDAC5 通路缓解 HepG2 细胞中的脂质积累。此外,敲除 HDAC5 可上调 ABCG5 的表达,促进 HepG2 细胞中胆固醇的排泄。总之,我们的研究为了解母体高脂饮食如何通过丁酸盐-AMPK-pHDAC5途径抑制断奶后代肝脏胆固醇排泄并下调ABCG5提供了新的见解。
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来源期刊
Clinical science
Clinical science 医学-医学:研究与实验
CiteScore
11.40
自引率
0.00%
发文量
189
审稿时长
4-8 weeks
期刊介绍: Translating molecular bioscience and experimental research into medical insights, Clinical Science offers multi-disciplinary coverage and clinical perspectives to advance human health. Its international Editorial Board is charged with selecting peer-reviewed original papers of the highest scientific merit covering the broad spectrum of biomedical specialities including, although not exclusively: Cardiovascular system Cerebrovascular system Gastrointestinal tract and liver Genomic medicine Infection and immunity Inflammation Oncology Metabolism Endocrinology and nutrition Nephrology Circulation Respiratory system Vascular biology Molecular pathology.
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