Low-dose valine attenuates diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) in mice by enhancing leptin sensitivity and modulating the gut microbiome

IF 7 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2024-11-01 DOI:10.1016/j.molmet.2024.102059

Felicianna , Emily K.K. Lo , Congjia Chen , Marsena J. Ismaiah , Fangfei Zhang , Hoi Kit Matthew Leung , Hani El-Nezami

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引用次数: 0

Abstract

Objectives

Elevated circulating branched-chain amino acids (BCAAs) have been associated with obesity, insulin resistance, and MASLD. Nonetheless, BCAA supplementation has been shown to provide protective outcomes towards the intervention of MASLD. Currently, there is a lack of study towards the contribution of the BCAA: valine on MASLD. Herein, the effect of low-dose valine supplementation was investigated for its role in the progression of MASLD.

Methods

C57BL/6J mice were fed a high-fat/high-cholesterol diet (HFD) to induce MASLD. Upon the establishment of MASLD, valine was supplemented via voluntary oral administration. Clinical and biochemical parameters associated with MASLD were measured, and molecular mechanism and gut microbiota modulation from the effect of valine were investigated.

Results

Low-dose valine was found to attenuate the progression of MASLD, significantly reducing the gain in body weight, liver weight, and epididymal white adipose tissue (eWAT) weight, while also attenuating hyperglycemia and hyperleptinemia, and improving serum lipid profiles. Mechanistically, in the liver, genes related to hepatic lipogenesis and cholesterol biosynthesis were downregulated, while those associated with fatty acid oxidation, autophagy, and antioxidant capacity were upregulated, and AMPK pathway activity was enhanced. Liver and hypothalamic leptin resistance and inflammation were also attenuated, allowing better appetite control in mice fed a HFD and leading to reduced food intake. Additionally, metabolic flexibility in the eWAT was improved, and the gut microbiome was modulated by low-dose valine supplementation.

Conclusion

Low-dose valine supplementation attenuates MASLD by enhancing systemic leptin sensitivity and modulating the gut microbiome.

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低剂量缬氨酸通过提高瘦素敏感性和调节肠道微生物组减轻饮食诱发的小鼠代谢功能障碍相关性脂肪肝（MASLD）。

循环支链氨基酸（BCAA）的升高与肥胖、胰岛素抵抗和MASLD有关，但补充BCAA已被证明对干预MASLD具有保护作用。目前，关于 BCAA（缬氨酸）对 MASLD 的影响还缺乏研究。本研究调查了在高脂/高胆固醇饮食（HFD）模型中补充低剂量缬氨酸对 MASLD 的影响。研究发现，低剂量缬氨酸可减轻 MASLD 的进展，显著降低体重、肝脏重量和 eWAT 重量，减轻高血糖症状并改善血清脂质状况。它还能降低高瘦素血症，增强下丘脑瘦素敏感性，从而减少食物摄入量。在 eWAT 中，脂肪生成相关基因表达上调，瘦素表达受到抑制，这表明代谢灵活性得到改善。在肝脏中，缬氨酸改善了肝脏瘦素敏感性，减轻了肝脏脂肪变性，降低了甘油三酯、胆固醇、TNFα和IL-6水平。从机理上讲，缬氨酸能提高肝脏抗氧化能力，调节脂质代谢和抗氧化途径，下调新生脂肪生成和胆固醇合成，同时增加脂肪酸氧化和自噬相关基因的表达。此外，肝脏 AMPK 通路的活性也得到了增强，有助于改善瘦素敏感性和信号传导。此外，低剂量缬氨酸补充剂还能调节肠道微生物组，这表明有一种多方面的方法可以控制 MASLD。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.