Involvement of KLF11 in hepatic glucose metabolism in mice via suppressing of PEPCK-C expression

Huabing Zhang; Qi Chen; Tao Jiao; Anfang Cui; Xiujing Sun; Weijun Fang; Liwei Xie; Yang Liu; Fude Fang; Yongsheng Chang

doi:10.1371/journal.pone.0089552

Involvement of KLF11 in hepatic glucose metabolism in mice via suppressing of PEPCK-C expression

PLoS One. 2014 Feb 26;9(2):e89552. doi: 10.1371/journal.pone.0089552. eCollection 2014.

Authors

Huabing Zhang¹, Qi Chen², Tao Jiao², Anfang Cui³, Xiujing Sun⁴, Weijun Fang⁵, Liwei Xie⁶, Yang Liu⁷, Fude Fang², Yongsheng Chang²

Affiliations

¹ Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China ; National Laboratory of Medical Molecular Biology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
² National Laboratory of Medical Molecular Biology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
³ Department of Biochemistry, Jining Medical University, Jining, China.
⁴ Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing Digestive Disease Center, Beijing, China.
⁵ Department of Chemistry, School of Basic Medicine, Anhui Medical University, Hefei, China.
⁶ Integrative and Molecular Physiology, University of Michigan, Ann Arbor, Michigan, United States of America.
⁷ Department of Endocrinology, The Hospital Affiliated to Liaoning University of Traditional Chinese Medicine, Shenyang, China.

Abstract

Background: Abnormal hepatic gluconeogenesis is related to hyperglycemia in mammals with insulin resistance. Despite the strong evidences linking Krüppel-like factor 11 (KLF11) gene mutations to development of Type 2 diabetes, the precise physiological functions of KLF11 in vivo remain largely unknown.

Results: In current investigation, we showed that KLF11 is involved in modulating hepatic glucose metabolism in mice. Overexpression of KLF11 in primary mouse hepatocytes could inhibit the expression of gluconeogenic genes, including phosphoenolpyruvate carboxykinase (cytosolic isoform, PEPCK-C) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), subsequently decreasing the cellular glucose output. Diabetic mice with overexpression of KLF11 gene in livers significantly ameliorated hyperglycemia and glucose intolerance; in contrast, the knockdown of KLF11 expression in db/m and C57BL/6J mice livers impaired glucose tolerance.

Conclusions: Our data strongly indicated the involvement of KLF11 in hepatic glucose homeostasis via modulating the expression of PEPCK-C.

Publication types

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

MeSH terms

Animals
Apoptosis Regulatory Proteins
Blotting, Western
Cells, Cultured
DNA-Binding Proteins / antagonists & inhibitors
DNA-Binding Proteins / physiology*
Diabetes Mellitus, Experimental / physiopathology*
Diabetes Mellitus, Type 2 / physiopathology*
Gluconeogenesis
Glucose / metabolism*
Hep G2 Cells
Hepatocytes / metabolism
Hepatocytes / pathology*
Humans
Hyperglycemia / metabolism
Hyperglycemia / pathology*
Insulin Resistance
Male
Mice
Mice, Inbred C57BL
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Protein Serine-Threonine Kinases / genetics*
Protein Serine-Threonine Kinases / metabolism
RNA, Messenger / genetics
RNA, Small Interfering / genetics
Real-Time Polymerase Chain Reaction
Repressor Proteins
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors / antagonists & inhibitors
Transcription Factors / genetics
Transcription Factors / metabolism
Transcription Factors / physiology*

Substances

Apoptosis Regulatory Proteins
DNA-Binding Proteins
KLF11 protein, mouse
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Ppargc1a protein, mouse
RNA, Messenger
RNA, Small Interfering
Repressor Proteins
Transcription Factors
phosphoenolpyruvate carboxylase kinase
Protein Serine-Threonine Kinases
Glucose

Grants and funding

This work was supported by Peking Union Medical College (PUMC) Youth Fund and the Fundamental Research Funds for the Central Universities (3332013108), the National Natural Science Foundation of China (31371193 and 30872992), and the Scientific Research of BSKY (XJ201301) and the University’s Research Fund (2013×kj004) of Anhui Medical University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.