AICAR-Induced Activation of AMPK Inhibits TSH/SREBP-2/HMGCR Pathway in Liver

Shudong Liu; Fei Jing; Chunxiao Yu; Ling Gao; Yejun Qin; Jiajun Zhao

doi:10.1371/journal.pone.0124951

AICAR-Induced Activation of AMPK Inhibits TSH/SREBP-2/HMGCR Pathway in Liver

PLoS One. 2015 May 1;10(5):e0124951. doi: 10.1371/journal.pone.0124951. eCollection 2015.

Authors

Shudong Liu¹, Fei Jing², Chunxiao Yu², Ling Gao³, Yejun Qin⁴, Jiajun Zhao⁵

Affiliations

¹ Department of Endocrinology, Provincial Hospital Affiliated to Shandong University, Jinan, China; Department of Endocrinology, Shandong Rongjun General Hospital, Jinan, China.
² Department of Endocrinology, Provincial Hospital Affiliated to Shandong University, Jinan, China.
³ Central Laboratory, Provincial Hospital Affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.
⁴ Department of Pathology, Provincial Hospital Affiliated to Shandong University, Jinan, China.
⁵ Department of Endocrinology, Provincial Hospital Affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.

Abstract

Our previous study found that thyroid-stimulating hormone promoted sterol regulatory element-binding protein-2 (SREBP-2) expression and suppressed AMP-activated protein kinase (AMPK) activity in the liver, but it was unclear whether there was a direct link between TSH, AMPK and SREBP-2. Here, we demonstrate that the 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR)-induced activation of AMPK directly inhibited the expression of SREBP-2 and its target genes HMGCR and HMGCS, which are key enzymes in cholesterol biosynthesis, and suppressed the TSH-stimulated up-regulation of SREBP-2 in HepG2 cells; similar results were obtained in TSH receptor knockout mice. Furthermore, AMPK, an evolutionally conserved serine/threonine kinase, phosphorylated threonine residues in the precursor and nuclear forms of SREBP-2, and TSH interacted with AMPK to influence SREBP-2 phosphorylation. These findings may represent a molecular mechanism by which AMPK ameliorates the hepatic steatosis and hypercholesterolemia associated with high TSH levels in patients with subclinical hypothyroidism (SCH).

Publication types

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

MeSH terms

AMP-Activated Protein Kinases / metabolism*
Aminoimidazole Carboxamide / analogs & derivatives*
Aminoimidazole Carboxamide / pharmacology
Animals
Enzyme Activation / drug effects
Fluorescent Antibody Technique
Hep G2 Cells
Humans
Hydroxymethylglutaryl-CoA Synthase / metabolism
Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent / metabolism*
Liver / drug effects
Liver / enzymology*
Liver / metabolism
Liver / pathology
Mice, Knockout
Models, Biological
Phosphorylation / drug effects
Phosphothreonine / metabolism
Receptors, Thyrotropin / metabolism
Ribonucleotides / pharmacology*
Signal Transduction / drug effects*
Sterol Regulatory Element Binding Protein 2 / metabolism*
Thyrotropin / metabolism*
Thyrotropin / pharmacology
Up-Regulation / drug effects

Substances

Receptors, Thyrotropin
Ribonucleotides
Sterol Regulatory Element Binding Protein 2
Phosphothreonine
Aminoimidazole Carboxamide
Thyrotropin
Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent
Hydroxymethylglutaryl-CoA Synthase
AMP-Activated Protein Kinases
AICA ribonucleotide

Grants and funding

This work was supported by grants from the National Basic Research Program (2012CB524900), and the National Natural Science Foundation (81230018, 81430020, 81170794, 81270869, 81400828, 81471006). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.