Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin

Abstract

The obesity epidemic has led to an increased incidence of non–alcoholic fatty liver disease (NAFLD) and type 2 diabetes. AMP–activated protein kinase (Ampk) regulates energy homeostasis and is activated by cellular stress, hormones and the widely prescribed anti–type 2 diabetic drug metformin1,2. Ampk phosphorylates murine acetyl–CoA carboxylase3,4 (Acc) 1 at Ser79 and Acc2 at Ser212, inhibiting the conversion of acetyl–CoA to malonyl–CoA, a precursor in fatty acid synthesis5 as well as an allosteric inhibitor of fatty acid transport into mitochondria for oxidation6. To test the physiological impact of these phosphorylation events we generated mice with alanine knock–in mutations in both Acc1 (Ser79) and Acc2 (Ser212) (Acc double knock–in, AccDKI). These mice have elevated lipogenesis and lower fatty acid oxidation compared to wild–type (WT) mice, which contribute to the progression of insulin resistance, glucose intolerance and NAFLD, but not obesity. Remarkably, AccDKI mice made obese by high–fat feeding, are refractory to the lipid–lowering and insulin–sensitizing effects of metformin. These findings establish that inhibitory phosphorylation of Acc by Ampk is essential for the control of lipid metabolism, and in the setting of obesity, for metformin–induced improvements in insulin action.

Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?

“…Indeed, Fullerton et al, have shown that mutations in both acetyl-CoA carboxylase 1 and 2 (ACC 1, ACC2) promote lipogenesis and decrease lipid oxidation. These mutations led to the inability of AMPK-activated protein kinase (AMPK) to phosphorylate ACC1 and 2 and thus inactivate these enzymes (Fullerton et al, 2013). Therefore, in this case, impaired lipid oxidation led to increased hepatic lipid content and hepatic insulin resistance.…”

AMPK β1 reduces tumor progression and improves survival in p53 null mice

“…ACC is an important enzyme regulating lipogenesis and is inhibited by AMPK following phosphorylation at Ser79 (Fullerton et al ., 2013; Munday et al ., 1988). We found that consistent with reductions in AMPK activating phosphorylation, there was a reduction of approximately 50% in phosphorylation of ACC at Ser79 compared to the p53−/− AMPK β1+/+ tumors (Fig.…”

“…To directly evaluate the importance of AMPK phosphorylation of ACC in regulating cellular proliferation, we examined MEFs derived from mice with Ser‐Ala‐knock‐in mutations in the AMPK phosphorylation site on ACC1 (S79A) and ACC2 (S212A) (ACC DKI), which makes ACC constitutively active and increases rates of lipogenesis (Fullerton et al ., 2013). We found that MEFs derived from ACC DKI mice had increased proliferation rates by 1.9‐fold compared to WT controls (Fig.…”

“…Proliferation data from the ACC DKI MEFs or cells treated with lipogenesis inhibitors corroborated these results, suggesting that AMPK control of lipogenesis, through ACC inhibition, is important for limiting cellular proliferation. These data are in agreement with previous studies indicating that hepatocytes (Dzamko et al ., 2010) and macrophages (Fullerton et al ., 2015) from AMPK β1‐deficient mice have increased lipid synthesis and that activation of AMPK using A769662 or metformin lowers lipogenesis through an AMPK β1‐dependent pathway requiring the phosphorylation of ACC (Fullerton et al ., 2013). These data are also consistent with recent studies indicating that inhibiting lipogenesis, by mimicking AMPK phosphorylation of ACC using small molecules (Svensson et al ., 2016) or through chemical inhibition of fatty acid synthase (Menendez and Lupu, 2007; Orita et al ., 2008), is effective for limiting cellular proliferation.…”

“…Rates of fatty acid synthesis are governed by the expression of ATP‐citrate lyase (ACLY), acetyl‐CoA carboxylase (ACC), and fatty acid synthase (FAS) (Hanahan and Weinberg, 2011; Hirschey et al ., 2015; Shah et al ., 2016; Svensson et al ., 2016; Villani et al ., 2016). While AMPK may regulate multiple branches of the lipogenic pathway, direct phosphorylation of ACC has been shown to result in the inhibition of ACC activity, thereby preventing the conversion of acetyl‐CoA to malonyl‐CoA and blocking the entire lipogenic program (Fullerton et al ., 2013; Munday et al ., 1988). As such, AMPK may exert antiproliferative effects through both inhibition of lipogenesis and by inhibiting cell cycle progression.…”