期刊
BIOCHEMICAL JOURNAL
卷 468, 期 -, 页码 125-132出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20150125
关键词
aspirin; acetyl-CoA carboxylase; salsalate; non-alcoholic fatty liver disease; type 2 diabetes
资金
- Canadian Diabetes Association [OG-1-09-2698-65]
- Canadian Institute for Health Research (CIHR) [MOP-11480, BPF-112934]
- Canadian Foundation for Innovation [2008M00051]
- Canadian Liver Foundation
- Australian Research Council [DP130104548]
- National Health and Medical Research Council [APP1085460, APP1049197]
- Victorian Government
- Sanofi
Metformin is the mainstay therapy for type 2 diabetes (T2D) and many patients also take salicylate-based drugs [i. e., aspirin (ASA)] for cardioprotection. Metformin and salicylate both increase AMP-activated protein kinase (AMPK) activity but by distinct mechanisms, with metformin altering cellular adenylate charge (increasing AMP) and salicylate interacting directly at the AMPK beta 1 drug-binding site. AMPK activation by both drugs results in phosphorylation of ACC (acetyl-CoA carboxylase; P-ACC) and inhibition of acetyl-CoA carboxylase (ACC), the rate limiting enzyme controlling fatty acid synthesis (lipogenesis). We find doses of metformin and salicylate used clinically synergistically activate AMPK in vitro and in vivo, resulting in reduced liver lipogenesis, lower liver lipid levels and improved insulin sensitivity in mice. Synergism occurs in cell-free assays and is specific for the AMPK beta 1 subunit. These effects are also observed in primary human hepatocytes and patients with dysglycaemia exhibit additional improvements in a marker of insulin resistance (proinsulin) when treated with ASA and metformin compared with either drug alone. These data indicate that metformin-salicylate combination therapy may be efficacious for the treatment of non-alcoholic fatty liver disease (NAFLD) and T2D.
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