MedElevator
Войти в исследования Arab journal of gastroenterology : the official publication of the Pan-Arab Association of Gastroenterology · 2025
Depletion of FOXO4 promotes the development of nonalcoholic fatty liver disease by aggravating high-fat diet-induced liver injury by increasing SPP1 expression.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Huang Li, Qian Guanghui, Zhang Aimin, Xu Lei, Wang Shuhui, Gao Yang, Li Wenjie, Wang Duane, Hou Miao, Lv Haitao
Аннотация
BACKGROUND AND STUDY AIMS: Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition worldwide. Although forkhead box O4 (FOXO4) is implicated in liver diseases, its role in NAFLD remains unclear.
MATERIAL AND METHODS: FOXO4 knockout mice were generated using CRISPR/Cas9 and fed a normal or high-fat diet (NFD/HFD). Human hepatic stellate cell line (LX-2) cells were transfected in vitro with a FOXO4 siRNA plasmid.
RESULTS: Twelve weeks of HFD feeding downregulated FOXO4 expression and reduced its colocalization with hepatocyte nuclear factor 4α (HNF4α). HFD-fed mice exhibited increased liver-to-body weight ratios; marked lipid/glycogen accumulation; and elevated serum alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglyceride, and nonesterified fatty acid levels. These pathological manifestations were further exacerbated upon genetic ablation of FOXO4. Specifically, FOXO4 knockout aggravated HFD-induced upregulation of α-smooth muscle actin protein; increased the expression of profibrotic genes (including collagen type I alpha 1 chain, transforming growth factor-β1, and tissue inhibitor of metalloproteinases 1) and inflammatory mediators (such as interleukin-1β, IL-6, and tumour necrosis factor-α); and increased hepatocyte apoptosis. Mechanistically, FOXO4 suppressed secreted phosphoprotein 1 (SPP1) expression in LX-2 cells via direct binding to the SPP1 promoter and transcriptional suppression of its activity.
CONCLUSION: FOXO4 downregulation exacerbates HFD-induced NAFLD progression via SPP1-dependent steatosis, inflammation, and fibrosis, thereby suggesting its potential as a therapeutic target.
MATERIAL AND METHODS: FOXO4 knockout mice were generated using CRISPR/Cas9 and fed a normal or high-fat diet (NFD/HFD). Human hepatic stellate cell line (LX-2) cells were transfected in vitro with a FOXO4 siRNA plasmid.
RESULTS: Twelve weeks of HFD feeding downregulated FOXO4 expression and reduced its colocalization with hepatocyte nuclear factor 4α (HNF4α). HFD-fed mice exhibited increased liver-to-body weight ratios; marked lipid/glycogen accumulation; and elevated serum alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglyceride, and nonesterified fatty acid levels. These pathological manifestations were further exacerbated upon genetic ablation of FOXO4. Specifically, FOXO4 knockout aggravated HFD-induced upregulation of α-smooth muscle actin protein; increased the expression of profibrotic genes (including collagen type I alpha 1 chain, transforming growth factor-β1, and tissue inhibitor of metalloproteinases 1) and inflammatory mediators (such as interleukin-1β, IL-6, and tumour necrosis factor-α); and increased hepatocyte apoptosis. Mechanistically, FOXO4 suppressed secreted phosphoprotein 1 (SPP1) expression in LX-2 cells via direct binding to the SPP1 promoter and transcriptional suppression of its activity.
CONCLUSION: FOXO4 downregulation exacerbates HFD-induced NAFLD progression via SPP1-dependent steatosis, inflammation, and fibrosis, thereby suggesting its potential as a therapeutic target.