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J Obes Eat Disord, 2017
ISSN: 2471-8203
August 23-24, 2017 | Toronto, Canada
allied
academies
INTERNATIONAL OBESITY, BARIATRIC AND
METABOLIC SURGERY SUMMIT AND EXPO
Xiao Cheng et al., J Obes Eat Disord, 3:2
DOI: 10.21767/2471-8203-C1-002
S
tatement of the Problem: MicroRNAs (miRNAs) are
non-coding RNAs with a length of 19 to 25 nt that
are involved in posttranscriptional gene regulation by
binding to the 3’-untranslated regions (3’-UTR) of targeted
mRNA and impacting diverse cellular processes, including
cell differentiation, energy metabolism and chronic
inflammation. MicroRNA-378a (miR-378a) has been
reported to regulate adipose tissue browning and cancer
development. However, its role in cellular stress signaling
and hepatic insulin resistance has not yet been investigated.
Findings: Here we reported that expression of hepatic miR-
378a was upregulated by metabolic inflammatory inducers,
such as high fructose feeding, bacterial lipopolysaccharide
(LPS) and inflammatory cytokine TNF
α
. The elevated miR-
378a subsequently targeted the 3’-UTR of PPAR
α
which
compromised mitochondrial fatty acid
β
-oxidation and
induced mitochondrial and ER stress. miR-378a was further
found to directly interact with the dsRNA binding motifs
within the dsRNA activated protein kinase PKR and activated
the kinase to sustain the inflammatory stress and blunt the
insulin signaling in the liver. Genetic depletion of miR-378a
rescued hepatocytes from mitochondrial and ER stress,
systemic inflammation and insulin resistance induced by
fructose and LPS. Conclusion & Significance: This study, for
the first time, demonstrates that miR-378a is a mediator
in metabolic inflammatory stress and contributes to the
onset of insulin resistance. It further unveils that certain
miRNA is capable of directly interacting with and activating
protein kinase PKR to sustain the stress signaling between
mitochondria and ER. This discovery greatly broadens the
physiological function of miRNAs by demonstrating that,
in addition to target genes on the mRNA level, miRNAs are
able to interact with RNA binding protein(s) and directly
exert its regulatory effect on the protein levels. Results from
this study may provide rationale for using miR-378a as a
pharmaceutical target in the prevention and treatment of
insulin resistance and related metabolic syndrome.
e:
qsu2@unl.eduMicroRNA-378 in metabolic inflammatory stress and hepatic insulin resistance
Xiao Cheng, Yongyan Song, Neetu Sud and Qiaozhu Su
University of Nebraska-Lincoln, USA