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Updated: Apr 13, 2026

Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method
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Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method

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

Shudong Liu1, Fei Jing2, Chunxiao Yu2

  • 1Department of Endocrinology, Provincial Hospital Affiliated to Shandong University, Jinan, China; Department of Endocrinology, Shandong Rongjun General Hospital, Jinan, China.

Plos One
|May 2, 2015
PubMed

Insights

AMP-activated protein kinase (AMPK) directly inhibits sterol regulatory element-binding protein-2 (SREBP-2) expression and cholesterol synthesis. This mechanism may explain how AMPK improves liver health in subclinical hypothyroidism.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Metabolic Research

Background:

  • Thyroid-stimulating hormone (TSH) was previously shown to increase sterol regulatory element-binding protein-2 (SREBP-2) and decrease AMP-activated protein kinase (AMPK) activity.
  • The direct molecular link between TSH, AMPK, and SREBP-2 remained unclear.

Purpose of the Study:

  • To investigate the direct relationship between AMPK activation and SREBP-2 expression.
  • To elucidate the role of AMPK in TSH-mediated regulation of cholesterol biosynthesis.
  • To explore the impact of AMPK on SREBP-2 phosphorylation.

Main Methods:

  • Utilized 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) to activate AMPK in HepG2 cells.
  • Examined the effects of AMPK activation on SREBP-2 and its target genes (HMGCR, HMGCS) expression.
  • Investigated TSH-induced SREBP-2 regulation in HepG2 cells and TSH receptor knockout mice.
  • Analyzed SREBP-2 phosphorylation at threonine residues by AMPK.

Main Results:

  • AICAR-induced AMPK activation directly inhibited SREBP-2 expression and its downstream targets involved in cholesterol synthesis.
  • AMPK activation suppressed TSH-stimulated SREBP-2 upregulation in HepG2 cells and in vivo.
  • AMPK was found to phosphorylate threonine residues on both precursor and nuclear SREBP-2.
  • TSH was observed to interact with AMPK, influencing SREBP-2 phosphorylation.

Conclusions:

  • AMPK activation directly inhibits SREBP-2 expression and cholesterol biosynthesis.
  • AMPK plays a crucial role in modulating TSH's effect on SREBP-2.
  • AMPK directly phosphorylates SREBP-2, suggesting a direct regulatory mechanism.
  • These findings provide a molecular basis for AMPK's beneficial effects on hepatic steatosis and hypercholesterolemia in subclinical hypothyroidism.

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