MiR-155 Has a Protective Role in the Development of Non-Alcoholic Hepatosteatosis in Mice
et al. (2013) MiR-155 Has a Protective Role in the Development of Non-Alcoholic Hepatosteatosis in
Mice. PLoS ONE 8(8): e72324. doi:10.1371/journal.pone.0072324
MiR-155 Has a Protective Role in the Development of Non-Alcoholic Hepatosteatosis in Mice
Ashley M. Miller 0
Derek S. Gilchrist 0
Jagtar Nijjar 0
Elisa Araldi 0
Cristina M. Ramirez 0
Christopher A. Lavery 0
Carlos Ferna ndez-Hernando 0
Iain B. McInnes 0
Mariola Kurowska-Stolarska 0
Massimo Federici, University of Tor Vergata, Italy
0 1 Institute of Cardiovascular & Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow , United Kingdom , 2 Institute of Infection , Immunity and Inflammation , College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow , United Kingdom , 3 Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine , New York , United States of America
Hepatic steatosis is a global epidemic that is thought to contribute to the pathogenesis of type 2 diabetes. MicroRNAs (miRs) are regulators that can functionally integrate a range of metabolic and inflammatory pathways in liver. We aimed to investigate the functional role of miR-155 in hepatic steatosis. Male C57BL/6 wild-type (WT) and miR-1552/2 mice were fed either normal chow or high fat diet (HFD) for 6 months then lipid levels, metabolic and inflammatory parameters were assessed in livers and serum of the mice. Mice lacking endogenous miR-155 that were fed HFD for 6 months developed increased hepatic steatosis compared to WT controls. This was associated with increased liver weight and serum VLDL/LDL cholesterol and alanine transaminase (ALT) levels, as well as increased hepatic expression of genes involved in glucose regulation (Pck1, Cebpa), fatty acid uptake (Cd36) and lipid metabolism (Fasn, Fabp4, Lpl, Abcd2, Pla2g7). Using miRNA target prediction algorithms and the microarray transcriptomic profile of miR-1552/2 livers, we identified and validated that Nr1h3 (LXRa) as a direct miR-155 target gene that is potentially responsible for the liver phenotype of miR-1552/2 mice. Together these data indicate that miR-155 plays a pivotal role regulating lipid metabolism in liver and that its deregulation may lead to hepatic steatosis in patients with diabetes.
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Funding: A.M. Miller is supported by a British Heart Foundation Intermediate Research Fellowship (FS/08/035/25309). D.S. Gilchrist is funded by Masterswitch (EU
FP7 project). M. Kurowska-Stolarska is supported by an Arthritis Research UK Career Development Grant. J. Nijjar is supported by a MRC PhD Fellowship. C.A.
Lavery is supported by a British Heart Foundation PhD Studentship. The funders had no role in study design, data collection and analysis, decision to publish, or
preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Non-alcoholic fatty liver disease (NAFLD) is an increasing
health problem in obese individuals in developed countries, and
recent studies suggest an association between the presence of
NAFLD and diabetes risk [1,2]. A spectrum of liver tissue
pathology exists, comprising hepatic steatosis characterized by the
deposition of lipid droplets in hepatocytes, through to
nonalcoholic steatohepatitis (NASH) associated with hepatocyte death,
inflammation and fibrosis. Advanced disease may progress to
cirrhosis and hepatocellular carcinoma (HCC).
The pathogenesis of NAFLD is often rationalized as a
doublehit, whereby diet-induced hepatocellular lipid accumulation
presents the first-hit, followed by a second-hit in which
proinflammatory mediators induce inflammation, hepatocellular
injury, and fibrosis [3]. Kupffer cell activation and recruitment
of monocytes into damaged liver facilitates pro-inflammatory
cytokine release that in turn promotes lipid accumulation,
increased inflammation and aberrant fibrosis. The
post-transcriptional gene regulatory mechanisms that integrate inflammation
and lipid dysregulation in NAFLD are currently poorly
understood but could offer significant therapeutic opportunity once
elucidated.
MicroRNAs (miRs) are small, non-coding, endogenous RNA
molecules (22 nucleotides long) that act as critical
post-transcriptional regulators of many biological processes. They function by
binding to complementary sequences in the 39UTRs of specific
target mRNAs, usually resulting in gene silencing [4]. Recently, a
role for miRNAs in liver disease has been proposed: hepatic
expression profiling has revealed temporal changes in miRNA
expression in human and murine NAFLD, and identified several
differentially expressed miRNAs including miR-21, miR-34a, and
miR-122 [5]. In addition, it has been shown that hepatic miR-155
expression was increased in murine models of NASH and HCC,
and its expression correlated with disease severity [6,7]. In line
with increased miR-155, the miR-155 target genes CCAAT/
enhancer-binding protein beta (Cebpb) (...truncated)