Rice Protein Peptides Alleviate Alcoholic Liver Disease via the PPARγ Signaling Pathway: Through Liver Metabolomics and Gut Microbiota Analysis

Alcoholic liver disease (ALD) is the predominant type
of liver
disease worldwide, resulting in significant mortality and a high disease
burden. ALD damages multiple organs, including the liver, gut, and
brain, causing inflammation, oxidative stress, and fat deposition.
In this study, we investigated the effects of rice protein peptides
(RPP) on ALD in mice with a primary focus on the gut microbiota and
liver metabolites. The results showed that administration of RPP significantly
alleviated the symptoms of ALD in mice including adiposity, oxidative
stress, and inflammation. The KEGG pathway shows that RPP downregulates
the liver metabolite of capric acid and the metabolism of fatty acid
biosynthesis compared with the MOD group. Mechanistically, RPP downregulated
the PPARγ signaling pathway and suppressed the expression of
fatty acid biosynthesis genes (FASN, ACC1, ACSL1, and ACSL3). Furthermore,
two active peptides (YLPTKQ and PKLPR) with potential therapeutic
functions for ALD were screened by Caco-2 cell modeling and molecular
docking techniques. In addition, RPP treatment alleviates gut microbiota
dysbiosis by reversing the F/B ratio, increasing the relative abundance
of Alloprevotella and Alistipes,
and upregulating the level of short-chain fatty acids. In conclusion,
RPP alleviates ALD steatosis through the PPARγ signaling pathway
by YLPTKQ and PKLPR and regulates gut microbiota.

酒精性肝病（Alcoholic Liver Disease, ALD）是全球范围内占主导地位的肝脏疾病类型，可引发较高的死亡率并造成沉重的疾病负担。ALD可损伤肝脏、肠道及大脑等多个器官，诱发炎症反应、氧化应激与脂肪沉积。本研究以小鼠为模型，探究了大米蛋白肽（rice protein peptides, RPP）对ALD的干预作用，重点关注肠道菌群与肝脏代谢物的变化。实验结果显示，给予RPP可显著缓解小鼠的ALD症状，包括脂肪堆积、氧化应激与炎症反应。KEGG通路分析表明，相较于模型组（MOD组），RPP可下调肝脏中癸酸的代谢水平，并抑制脂肪酸生物合成通路。机制层面，RPP可下调过氧化物酶体增殖物激活受体γ（PPARγ）信号通路的活性，并抑制脂肪酸生物合成相关基因（FASN、ACC1、ACSL1及ACSL3）的表达。此外，本研究通过Caco-2细胞模型与分子对接技术，筛选出两种具备ALD潜在治疗价值的活性肽（YLPTKQ与PKLPR）。此外，RPP干预可通过逆转F/B比值、提升异普雷沃菌属（Alloprevotella）与别样杆菌属（Alistipes）的相对丰度，并上调短链脂肪酸水平，从而改善肠道菌群失调。综上，RPP可通过YLPTKQ与PKLPR这两种活性肽，经由PPARγ信号通路缓解ALD相关脂肪变性，并调节肠道菌群稳态。