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 PPARα 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 β-oxidation in liver. Upregulated miR199a-5p in hepatocytes may contribute to impaired FA β-oxidation in mitochondria and aberrant lipid deposits, probably via CAV1 and the PPARα pathway.
Highlights
Non-alcoholic fatty liver disease (NAFLD), characterised by excessive fat deposits in the liver, is a risk factor for a variety of metabolic diseases including obesity, dyslipidaemia and type 2 diabetes
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 non-alcoholic fatty liver disease (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
To test the role of miR199a-5p in hepatic steatosis, HepG2 cells and AML12 hepatocytes were exposed to OA and PA, two abundant fatty acid (FA) in the serum of obese mice (Escande et al 2010), or the no oleate acid/ palmitate acid (OA/PA) control
Summary
Non-alcoholic fatty liver disease (NAFLD), characterised by excessive fat deposits in the liver, is a risk factor for a variety of metabolic diseases including obesity, dyslipidaemia and type 2 diabetes. Obesity, which commonly originates from overnutrition, has been considered to be the most prevalent cause of the development of NAFLD (Fabbrini et al 2010). It has been suggested that obesity-induced NAFLD in humans is associated with the suppression of several genes involved in the FA oxidation pathway (Wanless & Lentz 1990, Mitsuyoshi et al 2009)
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