The circFASN/miR-33a pathway participates in tacrolimus-induced dysregulation of hepatic triglyceride homeostasis View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2020-03-27

AUTHORS

Chenzhi Zhang, Kangchen Chen, Rongli Wei, Guanghan Fan, Xuechun Cai, Li Xu, Beini Cen, Jianguo Wang, Haiyang Xie, Shusen Zheng, Xiao Xu

ABSTRACT

Dyslipidemia exhibits a high incidence after liver transplantation, in which tacrolimus, a widely used immunosuppressant, plays a fundamental role. MicroRNAs and related circRNAs represent a class of noncoding RNAs that have been recognized as important regulators of genes associated with lipid metabolism. However, their transcriptional activities and functional mechanisms in tacrolimus-related dyslipidemia remain unclear. In this study, we observed that tacrolimus could induce triglyceride accumulation in hepatocytes by stimulating sterol response element-binding proteins (SREBPs) and miR-33a. Our in silico and experimental analyses identified miR-33a as a direct target of circFASN. Tacrolimus could downregulate circFASN and result in elevated miR-33a in vivo and in vitro. Overexpression of circFASN or silencing of miR-33a decreased the promoting effects of tacrolimus on triglyceride accumulation. Clinically, the incidence of dyslipidemia in liver transplant recipients with elevated serum miR-33a after liver transplantation was higher than that in patients without elevated serum miR-33a (46.3% vs. 18.8% p = 0.012, n = 73). Our results showed that the circFASN/miR-33a regulatory system plays a distinct role in tacrolimus-induced disruption of lipid homeostasis. MiR-33a is likely a risk factor for tacrolimus-related dyslipidemia, providing a potential therapeutic target to combat tacrolimus-induced dyslipidemia after liver transplantation. More... »

PAGES

23

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41392-020-0105-2

DOI

http://dx.doi.org/10.1038/s41392-020-0105-2

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1125922896

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/32296037


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32 schema:description Dyslipidemia exhibits a high incidence after liver transplantation, in which tacrolimus, a widely used immunosuppressant, plays a fundamental role. MicroRNAs and related circRNAs represent a class of noncoding RNAs that have been recognized as important regulators of genes associated with lipid metabolism. However, their transcriptional activities and functional mechanisms in tacrolimus-related dyslipidemia remain unclear. In this study, we observed that tacrolimus could induce triglyceride accumulation in hepatocytes by stimulating sterol response element-binding proteins (SREBPs) and miR-33a. Our in silico and experimental analyses identified miR-33a as a direct target of circFASN. Tacrolimus could downregulate circFASN and result in elevated miR-33a in vivo and in vitro. Overexpression of circFASN or silencing of miR-33a decreased the promoting effects of tacrolimus on triglyceride accumulation. Clinically, the incidence of dyslipidemia in liver transplant recipients with elevated serum miR-33a after liver transplantation was higher than that in patients without elevated serum miR-33a (46.3% vs. 18.8% p = 0.012, n = 73). Our results showed that the circFASN/miR-33a regulatory system plays a distinct role in tacrolimus-induced disruption of lipid homeostasis. MiR-33a is likely a risk factor for tacrolimus-related dyslipidemia, providing a potential therapeutic target to combat tacrolimus-induced dyslipidemia after liver transplantation.
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39 accumulation
40 activity
41 analysis
42 circRNAs
43 class
44 direct target
45 disruption
46 distinct roles
47 dyslipidemia
48 dysregulation
49 effect
50 effects of tacrolimus
51 element-binding protein
52 experimental analysis
53 factors
54 functional mechanisms
55 fundamental role
56 genes
57 hepatic triglyceride homeostasis
58 hepatocytes
59 high incidence
60 homeostasis
61 immunosuppressants
62 important regulator
63 incidence
64 incidence of dyslipidemia
65 lipid homeostasis
66 lipid metabolism
67 liver transplant recipients
68 liver transplantation
69 mechanism
70 metabolism
71 miR
72 miR-33a
73 microRNAs
74 overexpression
75 pathway
76 patients
77 potential therapeutic target
78 protein
79 recipients
80 regulator
81 regulatory system
82 response element-binding protein
83 results
84 risk factors
85 role
86 silencing
87 sterol response element-binding protein
88 study
89 system
90 tacrolimus
91 target
92 therapeutic target
93 transcriptional activity
94 transplant recipients
95 transplantation
96 triglyceride accumulation
97 triglyceride homeostasis
98 vivo
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