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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-04-13

AUTHORS

Pedro M Rodrigues, Marta B Afonso, André L Simão, Catarina C Carvalho, Alexandre Trindade, António Duarte, Pedro M Borralho, Mariana V Machado, Helena Cortez-Pinto, Cecília MP Rodrigues, Rui E Castro

ABSTRACT

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 (PPARα), 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/PPARα 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. More... »

PAGES

e2748-e2748

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/cddis.2017.172

DOI

http://dx.doi.org/10.1038/cddis.2017.172

DIMENSIONS

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PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28406477


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28 schema:description AbstractmicroRNAs 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 (PPARα), 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/PPARα 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.
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36 FF diet
37 NAFLD patients
38 OCA
39 PPARα axis
40 ablation
41 ablation results
42 abrogation
43 accumulation
44 acid uptake
45 activation
46 addition
47 axis
48 biopsy
49 cholesterol accumulation
50 damage
51 decrease
52 decreased expression
53 development
54 diet
55 disease
56 expression
57 fast food diet
58 fatty acid uptake
59 fatty liver disease
60 features
61 fibrosis
62 food diet
63 impairment
64 inflammation
65 insulin sensitivity
66 key molecular targets
67 knockout mice
68 levels
69 lipoapoptosis
70 lipoprotein metabolism
71 liver
72 liver damage
73 liver disease
74 metabolic parameters
75 metabolic syndrome
76 metabolism
77 miR-21 knockout mice
78 miR-21 levels
79 miR-21 targets
80 mice
81 minimal steatosis
82 model
83 molecular targets
84 muscle
85 muscle biopsy
86 muscle insulin sensitivity
87 nonalcoholic fatty liver disease
88 nonalcoholic steatohepatitis
89 nuclear receptors
90 oxidative stress
91 parameters
92 pathogenesis
93 patients
94 peroxisome proliferator-activated receptor α
95 pharmacological treatment
96 polyunsaturation
97 potential
98 progressive decrease
99 proliferator-activated receptor α
100 receptor α
101 receptors
102 regard
103 results
104 role
105 sensitivity
106 serum
107 specific pharmacological treatment
108 steatohepatitis
109 steatosis
110 stress
111 syndrome
112 target
113 therapeutic potential
114 therapy
115 treatment
116 typical models
117 uptake
118 whole-body metabolic parameters
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