AMP-activated protein kinase (AMPK) is a metabolic sensor in mammals that is activated when ATP levels in the cell decrease. AMPK is a heterotrimeric protein that comprises 3 subunits, each of which has multiple phosphorylation sites that play critical roles in the regulation of either anabolism or catabolism by directly phosphorylating proteins or modulating gene transcription in multiple pathways, such as synthesis, oxidation and lipolysis of lipid. Research focused on the phosphorylation sites that are involved in lipid metabolism will lead to a better recognition of the role of AMPK in therapeutics for several common diseases. In this review, close attention is paid to the recent research on the structure, and multisite phosphorylation of AMPK subunits, as well as AMPK regulation of lipid metabolism via phosphorylation of related molecules.

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).

Cholesterol homeostasis is critical and necessary for the body’s functions. Hypercholesterolemia can lead to significant clinical problems, such as cardiovascular disease (CVD). 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and low–density lipoprotein cholesterol receptor (LDLR) are major points of control in cholesterol homeostasis. We summarize the regulatory mechanisms of HMGCR and LDLR, which may provide insight for new drug design and development.

Autoimmune thyroid disease (AITD) and type 1 diabetes mellitus (T1DM) are two common autoimmune diseases that can occur concomitantly. In general, patients with diabetes have a high risk of AITD. It has been proposed that a complex genetic basis together with multiple nongenetic factors make a variable contribution to the pathogenesis of T1DM and AITD. In this paper, we summarize current knowledge in the field regarding potential pathogenic factors of T1DM and AITD, including human leukocyte antigen, autoimmune regulator, lymphoid protein tyrosine phosphatase, forkhead box protein P3, cytotoxic T lymphocyte-associated antigen, infection, vitamin D deficiency, and chemokine (C-X-C motif) ligand. These findings offer an insight into future immunotherapy for autoimmune diseases.

BackgroundMetformin, as the first-line treatment anti-diabetic drug, represents increasing evidence of a potential efficacy in improving dyslipidemia. However, the exact molecular mechanism(s) by which metformin influences lipid metabolism remains incompletely understood.MethodsThe HepG2 cells were treated with metformin and the AMP-activated protein kinase (AMPK) inhibitor compound C or a dominant-negative form of AMPK plasmid. ELISA assay was employed to measure AMPK activity, and cellular cholesterol content was determined by enzymatic colorimetric method. RT-PCR and western blotting were used to detect SREBP-2 mRNA levels and its target protein levels.ResultsWe found that metformin significantly stimulated AMPK activity and decreased intracellular total cholesterol contents in HepG2 cells. Metformin reduced the sterol regulatory element-binding protein-2 (SREBP-2) and its downstream target proteins and increased low-density lipoprotein receptor (LDLR) levels.ConclusionOur preliminary results demonstrate that metformin as a first-line and initial medication suppresses the synthesis of SREBP-2 and upregulates LDLR, and consequently decreases cholesterol production via activation of AMPK, at least partly. These findings suggest a therapeutic target and potential beneficial effects of metformin on the prevention of dyslipidemia or related diseases.

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Prior studies have demonstrated a close association between brain insulin resistance and Alzheimer’s disease (AD), while selenium supplementation was shown to improve insulin homeostasis in AD patients and to exert neuroprotective effects in a mouse model of AD. However, the mechanisms underlying the neuroprotective actions of selenium remain incompletely understood. In this study, we performed a label-free liquid chromatography-tandem mass spectrometry (LC–MS/MS) quantitative proteomics approach to analyze differentially expressed proteins (DEPs) in the hippocampus and cerebral cortex of Aβ precursor protein (APP)/presenilin-1 (PS1) mice following 2 months of treatment with sodium selenate. A total of 319 DEPs (205 upregulated and 114 downregulated proteins) were detected after selenium treatment. Functional enrichment analysis revealed that the DEPs were mainly enriched in processes affecting axon development, neuron differentiation, tau protein binding, and insulin/insulin-like growth factor type 1 (IGF1)-related pathways. These results demonstrate that a number of insulin/IGF1 signaling pathway-associated proteins are differentially expressed in ways that are consistent with reduced central insulin resistance, suggesting that selenium has therapeutic value in the treatment of neurodegenerative and metabolic diseases such as AD and non-alcoholic fatty liver disease (NAFLD).