MicroRNA-194 inhibition improves dietary-induced non-alcoholic fatty liver disease in mice through targeting on FXR

Abstract

Non-alcoholic fatty liver disease (NAFLD) affects obesity-associated metabolic syndrome, which exhibits hepatic steatosis, insulin insensitivity and glucose intolerance. Previous studies indicated that hepatic microRNAs (miRs) play critical roles in the development of NAFLD. In this study, we aim to explore the pathophysiological role of miR-194 in obesity-mediated metabolic dysfunction. Our findings show that the high fat diet or palmitic acid treatment significantly increase hepatic miR-194 levels in vivo and in vitro. Silence of miR-194 protects palmitic acid-induced inflammatory response in cultured hepatocytes, and attenuates structural disorders, lipid deposits and inflammatory response in fatty liver. MiR-194 inhibitor also improves glucose and insulin intolerance in obese mice. Through dual luciferase assay, we demonstrate that miR-194 directly binds to FXR/Nr1h4 3'-UTR, and inhibits gene expression of FXR/Nr1h4. Furthermore, overexpression of miR-194 downregulates FXR/Nr1h4 in cultured hepatocytes, but miR-194 inhibitor reversely increases FXR/Nr1h4 expression in obese mouse liver tissues. On the contrast, silence of FXR/Nr1h4 abolishes the hepatic benefits in obese mice treated with miR-194 inhibitor. Present study provides a novel finding that suppression of miR-194 attenuates dietary-induced NAFLD via upregulation of FXR/Nr1h4. The findings suggest miR-194/FXR are potential diagnostic markers and therapeutic targets for NAFLD.

MiR-455 targeting SOCS3 improve liver lipid disorders in diabetic mice

“…MicroRNAs play an important role in a variety of diseases [18][19][20] including the lipid metabolic disorder [21,22], because they can regulate a wide range of growth and development processes [7]. Recent studies indicate that miR-27a [23], miR-194 [24] and miR-146b [25] can target different genes to regulate the development of NAFLD. According to our previous research, miR-455 is the key regulator of BAT in the process of differentiation [9] and may have an effect on the regulation of lipid synthesis.…”

Update on FXR Biology: Promising Therapeutic Target?

“…The FXR activation by OCA treatment, in combination with miR-21 ablation, ameliorated the NASH-associated liver damage in mice [ 55 ]. MiR-194 directly binds to FXR 3′-untranslated region, thus, FXR upregulation by the inhibition of miR-194 contributes to the prevention of high-fat diet (HFD)-induced hepatic steatosis in mice [ 56 ]. The serum BA levels correlated with the disease severity in NAFLD, whereas the adiponectin levels were inversely correlated [ 57 ], supporting that treatment with FXR agonists and/or adiponectin activators may be of help for the prevention of NASH.…”

Farnesoid X receptor (FXR) as a potential therapeutic target in nonalcoholic fatty liver disease and associated syndromes

“…Эта регуляторная РНК вырабатывается в гепатоцитах в присутствии пальмитиновой кислоты и в условиях диеты с высоким содержанием жиров и, связываясь с 3'НТО мРНК гена FXR/NR1H4, ингибирует его экспрес-сию. Также продемонстрировано, что повышение экс-прессии miR-194 способно стимулировать продукцию гепатоцитами провоспалительных цитокинов ФНО (TNF) и ИЛ-6 (IL-6), что может вносить дополнительный вклад в развитие болезни [31].Ранее было показано, что miR-194 экспрессируется в ответ на активацию опухо-левого супрессорар 53, а принудительная экспрессия miR-194приводит к целому ряду противоопухолевых эффектов, таких как угнетение пролиферации клеток рака кишечника [32,33], предотвращение эпителиаль-но-мезенхимального перехода клеток глиомы [34] и по-давление синтеза белка MDM2 -ингибитора p53 [35]. Для ряда опухолей показан сниженный уровень экс-прессии miR-194, по-видимому, связанный с угнетением активности р53 из-за мутаций гена ТР53 или подавления его экспрессии [36,37].…”