AICAR-Induced Activation of AMPK Inhibits TSH/SREBP-2/HMGCR Pathway in Liver.
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).
Department of Endocrinology, Provincial Hospital Affiliated to Shandong University, Jinan, China; Department of Endocrinology, Shandong Rongjun General Hospital, Jinan, China.
Shudong
S
Liu
Department of Endocrinology, Provincial Hospital Affiliated to Shandong University, Jinan, China.
Fei
F
Jing
Department of Endocrinology, Provincial Hospital Affiliated to Shandong University, Jinan, China.
Chunxiao
C
Yu
Central Laboratory, Provincial Hospital Affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.
Ling
L
Gao
Department of Pathology, Provincial Hospital Affiliated to Shandong University, Jinan, China.
Yejun
Y
Qin
Department of Endocrinology, Provincial Hospital Affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.
Jiajun
J
Zhao
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D056945:Hep G2 Cells; D006801:Humans; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000378:metabolism; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D018345:Mice, Knockout; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D010769:Phosphothreonine / Q000378:metabolism; D011989:Receptors, Thyrotropin / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*; D013972:Thyrotropin / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D011989:Receptors, Thyrotropin; D012265:Ribonucleotides; D051782:Sterol Regulatory Element Binding Protein 2; D010769:Phosphothreonine; D000620:Aminoimidazole Carboxamide; D013972:Thyrotropin; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; D006904:Hydroxymethylglutaryl-CoA Synthase; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide