Aberrant mir199a-5p/caveolin1/PPARα axis in hepatic steatosis

Bo Li, Zhiguo Zhang, Huizhi Zhang, Kai Quan, Yan Lu, Dongsheng Cai, Guang Ning

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The prevalence of non-alcoholic fatty liver disease (NAFLD), a condition characterized by an excessive accumulation of triglycerides (TGs) in hepatocytes, has dramatically increased globally during recent decades. MicroRNAs (miRs) have been suggested to play crucial roles in many complex diseases and lipid metabolism. Our results indicated that miR199a-5p was remarkably upregulated in free fatty acid (FA)-treated hepatocytes. To investigate the role of miR199a-5p in the pathogenesis of fatty liver and the potential mechanism by which miR199a-5p regulates NAFLD, we first transfected two hepatocyte cell lines, HepG2 and AML12 cells, with agomiR199a-5p or antagomiR199a-5p. Our results indicated that miR199a-5p overexpression exacerbated deposition of FA and inhibited ATP levels and mitochondrial DNA (mtDNA) contents. Consistently, suppression of miR199a-5p partially alleviated deposition of FA and increased ATP levels and mtDNA contents. Moreover, miR199a-5p suppressed the expression of mitochondrial FA β-oxidation-related genes through inhibition of caveolin1 (CAV1) and the related peroxisome proliferator-activated receptor alpha (PPARα) pathway. Furthermore, suppression of CAV1 gene expression by CAV1 siRNA inhibited the PPARa signalling pathway. Finally, we examined the expression of miR199a-5p in liver samples derived from mice fed a high-fat diet, db/db mice, ob/ob mice and NAFLD patients, and found that miR199a-5p was upregulated while CAV1 and PPARA were downregulated in these systems, which was strongly indicative of the essential role of miR199a-5p in NAFLD. In summary, miR199a-5p plays a vital role in lipid metabolism, mitochondrial activity and mitochondrial b-oxidation in liver. Upregulated miR199a-5p in hepatocytes may contribute to impaired FA b-oxidation in mitochondria and aberrant lipid deposits, probably via CAV1 and the PPARα pathway.

Original languageEnglish (US)
Pages (from-to)393-403
Number of pages11
JournalJournal of Molecular Endocrinology
Volume53
Issue number3
DOIs
StatePublished - Oct 13 2014

Fingerprint

PPAR alpha
Hepatocytes
Fatty Acids
Liver
Mitochondrial DNA
Lipid Metabolism
Adenosine Triphosphate
Hep G2 Cells
High Fat Diet
Fatty Liver
MicroRNAs
Nonesterified Fatty Acids
Small Interfering RNA
Mitochondria
Triglycerides
Down-Regulation
Lipids
Gene Expression
Cell Line
Non-alcoholic Fatty Liver Disease

Keywords

  • Caveolin1
  • Fatty acid β-oxidation
  • miR199a-5p
  • Non-alcoholic fatty liver disease
  • PPAR

ASJC Scopus subject areas

  • Endocrinology
  • Molecular Biology
  • Medicine(all)

Cite this

Aberrant mir199a-5p/caveolin1/PPARα axis in hepatic steatosis. / Li, Bo; Zhang, Zhiguo; Zhang, Huizhi; Quan, Kai; Lu, Yan; Cai, Dongsheng; Ning, Guang.

In: Journal of Molecular Endocrinology, Vol. 53, No. 3, 13.10.2014, p. 393-403.

Research output: Contribution to journalArticle

Li, B, Zhang, Z, Zhang, H, Quan, K, Lu, Y, Cai, D & Ning, G 2014, 'Aberrant mir199a-5p/caveolin1/PPARα axis in hepatic steatosis', Journal of Molecular Endocrinology, vol. 53, no. 3, pp. 393-403. https://doi.org/10.1530/JME-14-0127
Li, Bo ; Zhang, Zhiguo ; Zhang, Huizhi ; Quan, Kai ; Lu, Yan ; Cai, Dongsheng ; Ning, Guang. / Aberrant mir199a-5p/caveolin1/PPARα axis in hepatic steatosis. In: Journal of Molecular Endocrinology. 2014 ; Vol. 53, No. 3. pp. 393-403.
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AU - Cai, Dongsheng

AU - Ning, Guang

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AB - The prevalence of non-alcoholic fatty liver disease (NAFLD), a condition characterized by an excessive accumulation of triglycerides (TGs) in hepatocytes, has dramatically increased globally during recent decades. MicroRNAs (miRs) have been suggested to play crucial roles in many complex diseases and lipid metabolism. Our results indicated that miR199a-5p was remarkably upregulated in free fatty acid (FA)-treated hepatocytes. To investigate the role of miR199a-5p in the pathogenesis of fatty liver and the potential mechanism by which miR199a-5p regulates NAFLD, we first transfected two hepatocyte cell lines, HepG2 and AML12 cells, with agomiR199a-5p or antagomiR199a-5p. Our results indicated that miR199a-5p overexpression exacerbated deposition of FA and inhibited ATP levels and mitochondrial DNA (mtDNA) contents. Consistently, suppression of miR199a-5p partially alleviated deposition of FA and increased ATP levels and mtDNA contents. Moreover, miR199a-5p suppressed the expression of mitochondrial FA β-oxidation-related genes through inhibition of caveolin1 (CAV1) and the related peroxisome proliferator-activated receptor alpha (PPARα) pathway. Furthermore, suppression of CAV1 gene expression by CAV1 siRNA inhibited the PPARa signalling pathway. Finally, we examined the expression of miR199a-5p in liver samples derived from mice fed a high-fat diet, db/db mice, ob/ob mice and NAFLD patients, and found that miR199a-5p was upregulated while CAV1 and PPARA were downregulated in these systems, which was strongly indicative of the essential role of miR199a-5p in NAFLD. In summary, miR199a-5p plays a vital role in lipid metabolism, mitochondrial activity and mitochondrial b-oxidation in liver. Upregulated miR199a-5p in hepatocytes may contribute to impaired FA b-oxidation in mitochondria and aberrant lipid deposits, probably via CAV1 and the PPARα pathway.

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