miR-21 ablation and obeticholic acid ameliorate nonalcoholic steatohepatitis in mice

• Published in: Cell death & disease 2017-04, Vol.8 (4), p.e2748-e2748
• Main Authors: Rodrigues, Pedro M, Afonso, Marta B, Simão, André L, Carvalho, Catarina C, Trindade, Alexandre, Duarte, António, Borralho, Pedro M, Machado, Mariana V, Cortez-Pinto, Helena, Rodrigues, Cecília MP, Castro, Rui E
• Format: Article
• Language: English
• Subjects: 13/2; 38/77; 631/337/384/331; 631/443/319; 631/92/436; 692/699/1503/1607/2751; 82/29; 96/95; Animals; Antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Chenodeoxycholic Acid - analogs & derivatives; Chenodeoxycholic Acid - pharmacology; Disease Models, Animal; Fast Foods - adverse effects; Immunology; Inflammation - etiology; Inflammation - genetics; Inflammation - metabolism; Inflammation - therapy; Life Sciences; Liver Cirrhosis - etiology; Liver Cirrhosis - genetics; Liver Cirrhosis - metabolism; Liver Cirrhosis - therapy; Liver diseases; Male; Mice; Mice, Knockout; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - therapy; Original; original-article; Pathogenesis; PPAR alpha - agonists; PPAR alpha - genetics; PPAR alpha - metabolism; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Rodents
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2017.172

microRNAs were recently suggested to contribute to the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a disease lacking specific pharmacological treatments. In that regard, nuclear receptors are arising as key molecular targets for the treatment of nonalcoholic steatohepatitis (NASH). Here we show that, in a typical model of NASH-associated liver damage, microRNA-21 (miR-21) ablation results in a progressive decrease in steatosis, inflammation and lipoapoptosis, with impairment of fibrosis. In a complementary fast food (FF) diet NASH model, mimicking features of the metabolic syndrome, miR-21 levels increase in both liver and muscle, concomitantly with decreased expression of peroxisome proliferator-activated receptor α (PPAR α ), a key miR-21 target. Strikingly, miR-21 knockout mice fed the FF diet supplemented with farnesoid X receptor (FXR) agonist obeticholic acid (OCA) display minimal steatosis, inflammation, oxidative stress and cholesterol accumulation. In addition, lipoprotein metabolism was restored, including decreased fatty acid uptake and polyunsaturation, and liver and muscle insulin sensitivity fully reinstated. Finally, the miR-21/PPAR α axis was found amplified in liver and muscle biopsies, and in serum, of NAFLD patients, co-substantiating its role in the development of the metabolic syndrome. By unveiling that miR-21 abrogation, together with FXR activation by OCA, significantly improves whole body metabolic parameters in NASH, our results highlight the therapeutic potential of nuclear receptor multi-targeting therapies for NAFLD.