MicroRNA-148a deficiency promotes hepatic lipid metabolism and hepatocarcinogenesis in mice

Li Cheng; Yahui Zhu; Han Han; Qiang Zhang; Kaisa Cui; Hongxing Shen; Jinxiang Zhang; Jun Yan; Edward Prochownik; Youjun Li

doi:10.1038/cddis.2017.309

MicroRNA-148a deficiency promotes hepatic lipid metabolism and hepatocarcinogenesis in mice

Cell Death Dis. 2017 Jul 13;8(7):e2916. doi: 10.1038/cddis.2017.309.

Authors

Li Cheng^{1

2}, Yahui Zhu^{1

2}, Han Han^{1

2}, Qiang Zhang^{1

2}, Kaisa Cui^{1

2}, Hongxing Shen^{1

2}, Jinxiang Zhang³, Jun Yan^{4

5}, Edward Prochownik⁶, Youjun Li^{1

2}

Affiliations

¹ Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China.
² Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China.
³ Department of Surgery, Wuhan Union Hospital, Wuhan 430022, China.
⁴ State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210008, China.
⁵ Collaborative Innovation Center for Genetics and Development, Shanghai 200438, China.
⁶ Division of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC and The Department of Microbiology and Molecular Genetics, The University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA.

Abstract

miRNAs are involved in many physiologic and disease processes by virtue of degrading specific mRNAs or inhibiting their translation. miR-148a has been implicated in the control of tumor growth and cholesterol and triglyceride homeostasis using in vitro or in vivo gene expression- and silencing-based approaches. Here miR-148a knockout (KO) mice were used to investigate the intrinsic role of miR-148a in liver physiology and hepatocarcinogenesis in mice. miR-148a downregulation was found to be correlated with poor clinical outcomes in hepatocellular carcinoma (HCC) patients. Under regular chow diet (RCD) or high fat diet (HFD), miR-148a deletion significantly accelerated DEN-induced hepatocarcinogenesis in mice. Mechanistically, miR-148a deletion promotes lipid metabolic disorders in mice. Moreover, restoration of miR-148a reversed these defects. Finally, miR-148a was found to directly inhibit several key regulators of hepatocarcinogenesis and lipid metabolism. These findings reveal crucial roles for miR-148a in the hepatic lipid metabolism and hepatocarcinogenesis. They further identify miR-148a as a potential therapeutic target for certain liver diseases, including cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Hepatocellular / chemically induced
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / mortality
Carcinoma, Hepatocellular / pathology*
Cell Line, Tumor
Cholesterol / blood
Diethylnitrosamine / toxicity
Down-Regulation
Hep G2 Cells
Humans
Hydroxymethylglutaryl CoA Reductases / chemistry
Hydroxymethylglutaryl CoA Reductases / genetics
Hydroxymethylglutaryl CoA Reductases / metabolism
Lipid Metabolism / physiology*
Liver / metabolism
Liver Neoplasms / chemically induced
Liver Neoplasms / genetics
Liver Neoplasms / pathology*
Male
Mice
Mice, Knockout
MicroRNAs / genetics*
MicroRNAs / metabolism
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / antagonists & inhibitors
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
Sirtuins / antagonists & inhibitors
Sirtuins / genetics
Sirtuins / metabolism
Survival Rate
Triglycerides / blood
Y-Box-Binding Protein 1 / genetics
Y-Box-Binding Protein 1 / metabolism

Substances

MicroRNAs
Mirn148 microRNA, mouse
PPARGC1A protein, human
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Triglycerides
Y-Box-Binding Protein 1
YBX1 protein, human
Diethylnitrosamine
Cholesterol
HMGCR protein, human
Hydroxymethylglutaryl CoA Reductases
Sirtuins

Abstract

Publication types

MeSH terms

Substances

Grants and funding