LXRα Promotes Hepatosteatosis in Part Through Activation of MicroRNA‐378 Transcription and Inhibition of Ppargc1β Expression

Zhang, Tianpeng; Duan, Jiangyan; Zhang, Lei; Li, Zhuoyu; Steer, Clifford J.; Yan, Guiqin; Song, Guisheng

doi:10.1002/hep.30301

Cited by 28 publications

(24 citation statements)

References 42 publications

(76 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The two mature strands, miR-378a-3p and miR-378a-5p, originate from the first intron of the peroxisome proliferator-activated receptor gamma, coactivator 1 beta (ppargc1b) gene encoding PGC-1β 12 , 13 . Different from other miRNAs, miR-378 possesses its own transcription machinery independent of its host gene 14 . A previous study combining database mining, EST extension, and 5′RACE and 3′RACE confirmed that the nuclear receptor Liver X receptor alpha (LXRα) is a transcription factor that regulates miR-378 14 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

LXR activation potentiates sorafenib sensitivity in HCC by activating microRNA-378a transcription

et al. 2020

View full text Add to dashboard Cite

Sorafenib resistance is a major obstacle to the treatment of advanced hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) are multifunctional regulators of gene expression with profound impact for human disease. Therefore, better understanding of the biological mechanisms of abnormally expressed miRNAs is critical to discovering novel, promising therapeutic targets for HCC treatment. This study aimed to investigate the role of miR-378a-3p in the sorafenib resistance of HCC and elucidate the underlying molecular mechanisms. Methods : A novel hub miR-378a-3p was identified based on miRNA microarray and bioinformatics analysis. The abnormal expression of miR-378-3p was validated in different HCC patient cohorts and sorafenib-resistant (SR) HCC cell lines. The functional role of miR-378a-3p and its downstream and upstream regulatory machinery were investigated by gain-of-function and loss-of-function assays in vitro and in vivo . Interactions among miR-378a-3p, LXRα, and IGF1R were examined by a series of molecular biology experiments. Then, the clinical relevance of miR-378a-3p and its targets were evaluated in HCC samples. HCC patient-derived xenograft (PDX) model was used to assess the therapeutic value of LXRα and its downstream miR-378a-3p. Results : miR-378a-3p expression was frequently reduced in established sorafenib-resistant HCC cell lines. The decreased miR-378a-3p levels correlated with poor overall survival of HCC patients following sorafenib treatment. miR-378a-3p overexpression induced apoptosis in SR HCC cells, whereas miR-378a-3p silencing exerted the opposite effects. IGF1R was identified as a novel target of miR-378a-3p. Furthermore, the primary miR-378 level was not consistent with its precursor miRNA level in SR HCC cells, which was attributed to the downregulation of exportin5 (XPO5) and subsequently reduced nuclear export of precursor miR-378 and restrained maturation of miR-378-3p. In this context, we combined an agonist GW3965 of liver X receptor alpha (LXRα), which functioned as a transcription activator of miRNA-378a, and its activation re-sensitized sorafenib-resistant cells to sorafenib treatment in vitro and in vivo . Conclusions : Our finding suggested decreased expression of XPO5 prevents maturation of miR-378a-3p, which leaded to the overexpression of IGF-1R and counteracted the effects of sorafenib-induced apoptosis. LXRα was able to activate miRNA-378a-3p transcription in HCC cells and could be a potential combinable treatment strategy with sorafenib to suppress HCC progression.

show abstract

Section: Introductionmentioning

confidence: 99%

“…Different from other miRNAs, miR-378 possesses its own transcription machinery independent of its host gene 14 . A previous study combining database mining, EST extension, and 5′RACE and 3′RACE confirmed that the nuclear receptor Liver X receptor alpha (LXRα) is a transcription factor that regulates miR-378 14 .…”

Section: Introductionmentioning

confidence: 99%

LXR activation potentiates sorafenib sensitivity in HCC by activating microRNA-378a transcription

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The expression of miRNAs is controlled by its own promoter sequence that can be bound and regulated by transcription factors. For instance, the transcription factor LXRα was proved to activate miR-378 expression by bind to its promoter region [47] and MYC could recruited DNMT3A to the promoter region of miR-200b and repress its expression [48]. In this study, we found that pluripotent factors SOX2 and ESRRB could promote miR-1343 activation, but did not affect the activity of miR-545.…”

Section: Discussionmentioning

confidence: 57%

Molecular network of miR-1343 regulates the pluripotency of porcine pluripotent stem cells via repressing OTX2 expression

et al. 2018

View full text Add to dashboard Cite

2019) Molecular network of miR-1343 regulates the pluripotency of porcine pluripotent stem cells via repressing OTX2 expression, RNA Biology, 16:1, 82-92, ABSTRACTPorcine OTX2 was found to be highly activated in porcine iPS cells (piPSCs) that were reported by different laboratories worldwide. To reveal the regulatory function of OTX2 in porcine reprogrammed cells, we screened porcine miRNA-seq databases and found two miRNAs, miR-1343 and miR-545, that could specifically bind to 3ʹUTR of OTX2 and suppress endogenous OTX2 expression in piPSCs. Knockdown of OTX2 by miR-1343 and miR-545 could significantly increase the expression of SOX2 and ESRRB, but did not alter the expressions of OCT4 and KLF4, and improve the pluripotency of piPSCs. The promoter-based assays showed that OTX2 potentially bound to the promoter region of SOX2 and ESRRB and suppressed their expression. On the other hand, SOX2 could interact with OTX2 promoter. Ectopic expression of SOX2 could significantly decrease OTX2 promoter activity, showing that there is a negative feedback loop between SOX2 and OTX2. Additionally, SOX2 and ESRRB significantly stimulated miR-1343 expression in piPSCs, but OTX2 down regulated the expression of miR-1343 in either direct or indirect manners. In summary, this study demonstrates that there is a regulatory network mediated by miR-1343, in which downregulation of OTX2 by miR-1343 can elevate the expression of pluripotent genes that were then sustain the pluripotency of piPSCs. ARTICLE HISTORY

show abstract

“…MiRNA has been implicated as a crucial regulator in metabolic diseases by silencing genes at the posttranscriptional level. Growing evidence demonstrated that a large number of miRNAs, such as miR-122, miR-378 and miR-34a, are involved in the pathogenesis of NAFLD [30,31]. However, whether miRNAs are involved in the uric acid-induced hepatocytes lipid accumulation is unclear.…”

Section: Discussionmentioning

confidence: 99%

Uric acid induced hepatocytes lipid accumulation through regulation of miR-149-5p/FGF21 axis

Chen¹,

Chen²,

Yang³

et al. 2020

BMC Gastroenterol

View full text Add to dashboard Cite

Background: Hyperuricemia is a major risk for non-alcoholic fatty liver disease. However, the mechanisms for this phenomenon are not fully understood. This study aimed to investigate whether microRNAs mediated the pathogenic effects of uric acid on non-alcoholic fatty liver disease. Methods: Microarray was used to determine the hepatic miRNA expression profiles of male C57BL/6 mice fed on standard chow diet, high fat diet (HFD), and HFD combined with uric acid-lowering therapy by allopurinol. We validated the expression of the most significant differentially expressed microRNAs and explored its role and downstream target in uric acid-induced hepatocytes lipid accumulation.Results: Microarray analysis and subsequent validation showed that miR-149-5p was significantly up-regulated in the livers of HFD-fed mice, while the expression was down-regulated by allopurinol therapy. MiR-149-5p expression was also significantly up-regulated in uric acid-stimulated hepatocytes. Over-expression of miR-149-5p significantly aggregated uric acid-induced triglyceride accumulation in hepatocytes, while inhibiting miR-149-5p ameliorated the triglyceride accumulation. Luciferase report assay confirmed that FGF21 is a target gene of miR-149-5p. Silencing FGF21 abolished the ameliorative effects of miR-149-5p inhibitor on uric acid-induced hepatocytes lipid accumulation, while overexpression of FGF21 prevented the lipid accumulation induced by miR-149-5p mimics. Conclusions: Uric acid significantly up-regulated the expression of miR-149-5p in hepatocytes and induced hepatocytes lipid accumulation via regulation of miR-149-5p/FGF21 axis.

show abstract

LXRα Promotes Hepatosteatosis in Part Through Activation of MicroRNA‐378 Transcription and Inhibition of Ppargc1β Expression

Cited by 28 publications

References 42 publications

LXR activation potentiates sorafenib sensitivity in HCC by activating microRNA-378a transcription

LXR activation potentiates sorafenib sensitivity in HCC by activating microRNA-378a transcription

Molecular network of miR-1343 regulates the pluripotency of porcine pluripotent stem cells via repressing OTX2 expression

Uric acid induced hepatocytes lipid accumulation through regulation of miR-149-5p/FGF21 axis

Contact Info

Product

Resources

About