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The antidiabetic drug metformin stimulates AMP-activated protein kinase (AMPK) activity in the liver and in skeletal muscle. To better understand the role of AMPK in the regulation of hepatic lipids, we studied the effect of metformin on AMPK and its downstream effector, acetyl-CoA carboxylase (ACC), as well as on lipid content in cultured human hepatoma HepG2 cells. Metformin increased Thr-172 phosphorylation of the α subunit of AMPK in a dose- and time-dependent manner. In parallel, phosphorylation of ACC at Ser-79 was increased, which was consistent with decreasing ACC activity. Intracellular triacylglycerol and cholesterol contents were also decreased. These effects of metformin were mimicked or completely abrogated by adenoviral-mediated expression of a constitutively active AMPKα or a kinase-inactive AMPKα, respectively. An insulin-resistant state was induced by exposing cells to 30 mm glucose as indicated by decreased phosphorylation of Akt and its downstream effector, glycogen synthase kinase 3α/β. Under these conditions, the phosphorylation of AMPK and ACC was also decreased, and the level of hepatocellular triacylglycerols increased. The inhibition of AMPK and the accumulation of lipids caused by high glucose concentrations were prevented either by metformin or by expressing the constitutively active AMPKα. The kinase-inactive AMPKα increased lipid content and blocked the ability of metformin to decrease lipid accumulation caused by high glucose concentrations. Taken together, these results indicate that AMPKα negatively regulates ACC activity and hepatic lipid content. Inhibition of AMPK may contribute to lipid accumulation induced by high concentrations of glucose associated with insulin resistance. Metformin lowers hepatic lipid content by activating AMPK, thereby mediating beneficial effects in hyperglycemia and insulin resistance. The antidiabetic drug metformin stimulates AMP-activated protein kinase (AMPK) activity in the liver and in skeletal muscle. To better understand the role of AMPK in the regulation of hepatic lipids, we studied the effect of metformin on AMPK and its downstream effector, acetyl-CoA carboxylase (ACC), as well as on lipid content in cultured human hepatoma HepG2 cells. Metformin increased Thr-172 phosphorylation of the α subunit of AMPK in a dose- and time-dependent manner. In parallel, phosphorylation of ACC at Ser-79 was increased, which was consistent with decreasing ACC activity. Intracellular triacylglycerol and cholesterol contents were also decreased. These effects of metformin were mimicked or completely abrogated by adenoviral-mediated expression of a constitutively active AMPKα or a kinase-inactive AMPKα, respectively. An insulin-resistant state was induced by exposing cells to 30 mm glucose as indicated by decreased phosphorylation of Akt and its downstream effector, glycogen synthase kinase 3α/β. Under these conditions, the phosphorylation of AMPK and ACC was also decreased, and the level of hepatocellular triacylglycerols increased. The inhibition of AMPK and the accumulation of lipids caused by high glucose concentrations were prevented either by metformin or by expressing the constitutively active AMPKα. The kinase-inactive AMPKα increased lipid content and blocked the ability of metformin to decrease lipid accumulation caused by high glucose concentrations. Taken together, these results indicate that AMPKα negatively regulates ACC activity and hepatic lipid content. Inhibition of AMPK may contribute to lipid accumulation induced by high concentrations of glucose associated with insulin resistance. Metformin lowers hepatic lipid content by activating AMPK, thereby mediating beneficial effects in hyperglycemia and insulin resistance. AMP-activated protein kinase (AMPK) 1The abbreviations used are: AMPK, AMP-activated protein kinase; Ad, adenoviral vector; CA-AMPK, constitutively active AMPK; DN-AMPK, dominant-negative AMPK; ACC, acetyl-CoA carboxylase; AICAR, 5-amino-4-imidazolecarboxamide riboside; GSK, glycogen synthase kinase; DMEM, Dulbecco's modified Eagle's medium; GFP, green fluorescent protein.1The abbreviations used are: AMPK, AMP-activated protein kinase; Ad, adenoviral vector; CA-AMPK, constitutively active AMPK; DN-AMPK, dominant-negative AMPK; ACC, acetyl-CoA carboxylase; AICAR, 5-amino-4-imidazolecarboxamide riboside; GSK, glycogen synthase kinase; DMEM, Dulbecco's modified Eagle's medium; GFP, green fluorescent protein. is a phylogenetically conserved intracellular energy sensor that has been implicated in the regulation of glucose and lipid homeostasis (1Hardie D.G. Endocrinology. 2003; 144: 5179-5183Crossref PubMed Scopus (832) Google Scholar, 2Kemp B.E. Stapleton D. Campbell D.J. Chen Z.P. Murthy S. Walter M. Gupta A. Adams J.J. Katsis F. van Denderen B. Jennings I.G. Iseli T. Michell B.J. Witters L.A. Biochem. Soc. Trans. 2003; 31: 162-168Crossref PubMed Google Scholar, 3Carling D. Trends Biochem. Sci. 2004; 29: 18-24Abstract Full Text Full Text PDF PubMed Scopus (957) Google Scholar, 4Ruderman N. Prentki M. Nat. Rev. Drug Discov. 2004; 3: 340-351Crossref PubMed Scopus (375) Google Scholar). AMPK is activated by physiological stimuli, such as exercise, muscle contraction, and hormones including adiponectin and leptin, as well as by pathological stresses, glucose deprivation, hypoxia, oxidative stress, and osmotic shock (2Kemp B.E. Stapleton D. Campbell D.J. Chen Z.P. Murthy S. Walter M. Gupta A. Adams J.J. Katsis F. van Denderen B. Jennings I.G. Iseli T. Michell B.J. Witters L.A. Biochem. Soc. Trans. 2003; 31: 162-168Crossref PubMed Google Scholar, 5Hardie D.G. Scott J.W. Pan D.A. Hudson E.R. FEBS Lett. 2003; 546: 113-120Crossref PubMed Scopus (712) Google Scholar). AMPK serine/threonine protein kinase is a heterotrimeric complex consisting of a catalytic subunit (α) and two regulatory subunits (β and γ) (5Hardie D.G. Scott J.W. Pan D.A. Hudson E.R. FEBS Lett. 2003; 546: 113-120Crossref PubMed Scopus (712) Google Scholar). Regulation of AMPK activity is complex; it involves allosteric activation by AMP, which increases during states of stress where ATP is depleted, and phosphorylation via the presumptive upstream activator AMPK kinase (6Shaw R.J. Kosmatka M. Bardeesy N. Hurley R.L. Witters L.A. DePinho R.A. Cantley L.C. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 3329-3335Crossref PubMed Scopus (1433) Google Scholar, 7Woods A. Johnstone S.R. Dickerson K. Leiper F.C. Fryer L.G. Neumann D. Schlattner U. Wallimann T. Carlson M. Carling D. Curr. Biol. 2003; 13: 2004-2008Abstract Full Text Full Text PDF PubMed Scopus (1332) Google Scholar, 8Lizcano J.M. Goransson O. Toth R. Deak M. Morrice N.A. Boudeau J. Hawley S.A. Udd L. Makela T.P. Hardie D.G. 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Once activated, AMPK phosphorylates its downstream substrates to reduce ATP-consuming anabolic pathways, including cholesterol, fatty acid, and triacylglycerol synthesis, and increases ATP-generating catabolic pathways, including fatty acid oxidation and lipolysis. Phosphorylation by AMPK of two key substrates, 3-hydroxy-3-methylglutaryl-coenzyme A reductase and acetyl-CoA carboxylase (ACC) (12Hardie D.G. Carling D. Eur. J. Biochem. 1997; 246: 259-273Crossref PubMed Scopus (1138) Google Scholar), which are the rate-limiting enzymes in cholesterol and fatty acid biosynthesis, respectively, results in their inactivation and thus reduces cellular ATP consumption during metabolic stress. Type II diabetes is associated with hyperinsulinemia and insulin resistance leading to elevated hepatic glucose production, hyperglycemia, and hyperlipidemia (13Gerich J.E. Endocr. Rev. 1998; 19: 491-503Crossref PubMed Scopus (0) Google Scholar, 14Winder W.W. Hardie D.G. Am. J. Physiol. 1999; 277: E1-E10PubMed Google Scholar). Administration of the AMPK activator, 5-amino-4-imidazolecarboxamide riboside (AICAR), improves glucose tolerance and lipid profiles in the insulin-resistant Zucker rat (15Buhl E.S. Jessen N. Pold R. Ledet T. Flyvbjerg A. Pedersen S.B. Pedersen O. Schmitz O. Lund S. Diabetes. 2002; 51: 2199-2206Crossref PubMed Scopus (208) Google Scholar), suggesting that AMPK activity regulates insulin sensitivity and the associated dyslipidemia. Metformin is an oral biguanide antidiabetic drug that improves insulin sensitivity and reduces plasma glucose and lipids in patients with type II diabetes (16Fedele D. Tiengo A. Nosadini R. Marchiori E. Briani G. Garotti M.C. Muggeo M. Diabetes Metab. 1976; Google Scholar, Diabetes Metab. Google Scholar, Am. J. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). In with hyperinsulinemia and hyperglycemia, metformin liver triacylglycerol and fatty acid and increases activity Diabetes Metab. 2002; PubMed Scopus Google Scholar). Metformin may insulin sensitivity of insulin as by increased phosphorylation of the insulin and insulin L. R. A. 2003; Google Scholar). the by which metformin lowers lipids is activation of AMPK by metformin has been to decrease glucose and fatty acid oxidation in the liver G. R. Chen J. M. J. T. N. N. J. PubMed Scopus Google Scholar, S.A. Hardie D.G. Diabetes. 2002; 51: PubMed Scopus Google Scholar). The were to the to which the effect of metformin on hepatocellular lipids is by AMPK and AMPK regulates lipid accumulation in insulin-resistant the cultured human hepatoma HepG2 as a and that AMPK as a of hepatocellular lipid content. Metformin increased ACC phosphorylation in an which in decreased intracellular triacylglycerol and cholesterol the ability of metformin to reduce lipids was mimicked by adenoviral-mediated expression of a constitutively active AMPKα and was blocked by a kinase-inactive AMPKα, suggesting that AMPK is for the of In exposing cells to high glucose concentrations induced a of insulin resistance in which AMPK was and lipids of the kinase-inactive AMPKα also to triacylglycerol suggesting a role for AMPK in lipid accumulation associated with insulin resistance. also a for to AMPK in insulin resistance and in type II and were triacylglycerol and cholesterol were The used to was and were AMPK the or were was and were was and to were Dulbecco's modified Eagle's and were were of hepatoma HepG2 cells were the Type HepG2 cells were cultured in and mm The cells were in a of at and by HepG2 cells were in with in to and in as S. D. G. J. 2004; PubMed Scopus Google Scholar, D.J. J.W. Eur. J. 1997; PubMed Scopus Google Scholar, K. K. S. S. M. T. K. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). were with metformin as indicated in the of and To during of metformin in was with the to the In was by the the as M. J. 2002; PubMed Scopus Google Scholar). Under the of of HepG2 cells with metformin the of AMPKα and ACC phosphorylation and the accumulation of triacylglycerol by high concentrations of HepG2 cells were in and in either or high glucose concentrations in the or of mm metformin for an metformin the of AMPK by high glucose concentrations. were to with AMPK and ACC respectively. and metformin lowers the lipid accumulation caused by high glucose concentrations. of intracellular triacylglycerols and cholesterol were as in the two as of a constitutively active of AMPKα the effect of metformin on ACC phosphorylation and HepG2 cells were with adenoviral or a constitutively active of in for by with or mm metformin for an expression of the is to ACC phosphorylation as well as ACC of the protein was by The phosphorylation of AMPK and ACC and expression of AMPK protein were by with the AMPKα ACC and respectively. are of at and inhibition of intracellular triacylglycerol and cholesterol contents by metformin was by expression of the the two as lipid accumulation induced by high glucose concentrations in an manner. HepG2 cells were with the either or a dominant-negative in for by with or mm metformin in either or high glucose concentrations for an the ability of metformin to AMPK and ACC is by the in cells to or high glucose concentrations. of the protein was by or respectively. The phosphorylation of AMPK and ACC was with the AMPKα or ACC and inhibition of lipid by metformin was abrogated by the the two as of by a of insulin HepG2 cells were in either concentrations of glucose mm or high concentrations of glucose mm for and the to insulin for was as K. K. S. S. M. T. K. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The phosphorylation of Akt and its was with Akt and and increases in the phosphorylation of Akt and respectively, the level in cells in glucose concentrations and In high glucose concentrations the phosphorylation of Akt as well as and was in the expression of Akt and protein or and adenoviral expressing green protein was used as a D. M. K. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The adenoviral expressing a dominant-negative of was a of to as D. M. K. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, D. K. R.A. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, J. O. M. Full Text Full Text PDF PubMed Scopus Google Scholar). To the adenoviral expressing a constitutively active of a rat of and a of acid was a The was in to the of the The was by with and with the adenoviral were with The was human cells. were on human cells and by two on The of was by the at HepG2 cells were with in was cells were with metformin for the indicated that within of with of HepG2 cells green fluorescent protein. was as M. A. R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). In HepG2 cells were in mm mm mm mm mm mm and was by at for at and the was used for and of lipid content. concentrations in were a protein of protein were by and to in a consisting of mm mm and The were blocked with in with and with by with were by the The of was a of and and cholesterol contents were in a and as of of cellular protein as S. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). In HepG2 cells were in and with either or high glucose concentrations in the or of were as and cholesterol in were to the for are as the the of the was a was Metformin AMPK and ACC and the of in HepG2 the phosphorylation state of the α subunit of AMPK by a AMPK In HepG2 cells to concentrations of metformin for phosphorylation of AMPKα at Thr-172 was by as as by metformin at in the expression of AMPKα protein was by with the concentrations used mm and in phosphorylation was at was a at Metformin caused a and in AMPKα with a at with caused by mm at To AMPK we the phosphorylation of its downstream that metformin induced phosphorylation of ACC at Ser-79 in a dose- and time-dependent which the of Thr-172 phosphorylation of AMPKα at and A and cells were with metformin for phosphorylation of ACC was increased by at mm and to at mm Metformin at mm the effect of metformin at mm caused a at and was for Metformin at mm caused a and in ACC phosphorylation Intracellular of triacylglycerol and cholesterol in HepG2 cells to metformin for and were also concentrations of metformin decreased intracellular triacylglycerol and cholesterol content at in a for in triacylglycerol and cholesterol content were at were at the metformin was a 30 and decrease in triacylglycerol content and a and decrease in cholesterol content at and and a of insulin resistance induced by high concentrations of glucose we the effects of these high glucose concentrations on the phosphorylation of AMPKα at on the phosphorylation of ACC at and on lipid of HepG2 cells to glucose decreased phosphorylation of AMPK and ACC a in AMPK protein and In with these in phosphorylation of AMPK and ACC, triacylglycerol content increased by in insulin-resistant a in cholesterol content and To metformin lipid accumulation induced by high glucose HepG2 cells were with either or high glucose concentrations in the or of metformin for with the phosphorylation of AMPKα and ACC was by metformin in concentrations of glucose and and the intracellular contents of triacylglycerol and cholesterol were by metformin and Moreover, the inhibition of AMPK and ACC phosphorylation in cells to high glucose concentrations was by metformin and with the intracellular contents of triacylglycerol that were increased by high glucose concentrations were by metformin and The of Metformin on by a of the role of the catalytic α subunit of AMPK in lipid we the effect of adenoviral-mediated expression of a constitutively active of on the in ACC phosphorylation and lipid adenoviral the protein that a and was at was as by for the at its and and In AMPK protein level was by the and ACC phosphorylation was in the state with the and was that the cells to metformin because expression of the the effect of metformin on ACC phosphorylation the effect in cells and to the effect of metformin in the also triacylglycerol and cholesterol by and the were by metformin and suggesting that is a effect of metformin and the on the phosphorylation of ACC and of The effect of the was also in cells to high concentrations of the effect on or of AMPK, the phosphorylation of ACC was increased, and the level in cells to high glucose concentrations was with that in cells to glucose concentrations and with and cells to high glucose concentrations elevated triacylglycerols level the level was that in cells with and to high glucose concentrations The also the cholesterol content in cells to high glucose cholesterol were by high glucose concentrations These results indicate that the expression of the the phosphorylation of ACC and lowers lipid accumulation caused by high glucose concentrations in insulin-resistant HepG2 thus the effect of Metformin by in an AMPK ACC and lipid content was by of a dominant-negative of AMPK activity was by adenoviral-mediated expression of a a which has a dominant-negative effect on and AMPK J. O. M. Full Text Full Text PDF PubMed Scopus Google Scholar). in with the increased expression of the subunit as by with or of the of AMPK and ACC in cells to glucose concentrations and these in cells to high glucose concentrations to the effect of high concentrations of cells expressing the an in the triacylglycerol and a in cholesterol content and These results that to high concentrations of glucose AMPK and ACC also that of AMPK by high concentrations of glucose to the in lipid content that insulin resistance caused by high concentrations of To AMPK activity is for metformin to ACC and lipids, HepG2 cells were with or by with either or high glucose concentrations in the or of metformin for In the effects of metformin on AMPK and ACC as well as on triacylglycerol and cholesterol were to the effects in cells as in the ability of metformin to AMPK and ACC was by the that metformin ACC phosphorylation in an manner. Moreover, metformin decreased the triacylglycerol content by in cells to or high glucose the expression of the the effect of metformin on triacylglycerols The also blocked the effect of metformin on cholesterol content in cells to or high glucose concentrations these that AMPK the effect of metformin on hepatic lipid content. The of was to the role of AMPK activation by metformin in the regulation of hepatocellular that metformin increased phosphorylation of AMPK and its downstream lipid ACC, also that its were mimicked by of a constitutively active AMPK In an AMPK dominant-negative AMPK blocked the in ACC phosphorylation and the decrease in lipid content of HepG2 cells caused by the antidiabetic in cells in which an state was induced by high glucose the effects of metformin were also mimicked by the or prevented by the These that the effects of metformin on hepatocellular lipids are by of AMPK and of has been to that the phosphorylation of the phosphorylation of the α is for AMPK activity (10Crute B.E. Seefeld K. Gamble J. Kemp B.E. Witters L.A. J. Biol. Chem. 1998; 273: 35347-35354Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar, 11Stein S.C. Woods A. Jones N.A. Davison M.D. Carling D. Biochem. 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ACC the of which as the for fatty acid as well as a of the rate-limiting for fatty acid The role of ACC in lipid has been by increased fatty acid oxidation and in in L. PubMed Scopus Google Scholar). that AMPK activation by either or metformin stimulates fatty acid and reduces and triacylglycerol in rat G. R. Chen J. M. J. T. N. N. J. PubMed Scopus Google Scholar, Seefeld K. Witters L.A. R.A. Biochem. J. 1999; PubMed Scopus Google Scholar). that the in caused by metformin in HepG2 which was with of ACC phosphorylation by be by increased fatty acid oxidation decreased fatty acid In to ACC, it is also that metformin regulates that fatty acid or such as regulatory which the lipid in the In and and protein expression of regulatory protein and enzymes is G. R. Chen J. M. J. T. N. N. J. PubMed Scopus Google Scholar). be to of the effect of metformin via the in ACC as well as the in triacylglycerols caused by were in the by of the DN-AMPK, it is that ACC is the of the decrease in is also by the that of the mimicked the in ACC phosphorylation and the decrease in triacylglycerols caused by In the AMPK activator, AICAR, of triacylglycerols and their in Seefeld K. Witters L.A. R.A. Biochem. J. 1999; PubMed Scopus Google Scholar). Metformin also decreased HepG2 content of The effect of metformin on cholesterol content may be by the that 3-hydroxy-3-methylglutaryl-coenzyme A the rate-limiting in cholesterol biosynthesis, is also and by AMPK D. Hardie D.G. FEBS Lett. PubMed Scopus Google Scholar). the decrease in the effect of metformin on cholesterol was mimicked by of the and blocked by the DN-AMPK, suggesting a of metformin on hepatocellular cholesterol via the effects of metformin on ACC and 3-hydroxy-3-methylglutaryl-coenzyme A reductase via AMPK its effects on lipid content of HepG2 cells. of Metformin in a of the of AMPK in the of metformin in insulin-resistant HepG2 cells were to high glucose concentrations for and resistance to insulin was by decreased Akt is in with the that high concentrations of glucose phosphorylation of of the insulin as well as of insulin and K. K. S. S. M. T. K. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of HepG2 cells to high glucose concentrations also decreased AMPK and ACC which was to in and as well as in G. A. T. Biochem. J. 2003; PubMed Scopus Google Scholar, T. N. A. B. J. F. B.J. 2004; PubMed Scopus Google Scholar). In high glucose concentrations increased the triacylglycerol content of HepG2 the role of ACC in hepatocellular triacylglycerol is that of the also increased triacylglycerol content of HepG2 cells. the role of decreased ACC which increased in cells as well as to high glucose concentrations as an for the increased triacylglycerol content. in AMPK expression in of insulin suggesting that in phosphorylation of AMPK were the of the effects of high glucose concentrations on triacylglycerol In to cholesterol content in HepG2 cells to high concentrations of suggesting that the in AMPK and ACC phosphorylation were to the was also in the in cholesterol content that in to of the Metformin the decrease in phosphorylation of AMPK and ACC caused by high glucose and the elevated triacylglycerol in cells to high glucose concentrations to that were in cells to glucose concentrations. The effects of metformin be to in AMPK, as were completely abrogated by of the and mimicked by the is that the effects of metformin are also by the expression of enzymes that lipid biosynthesis, such as fatty acid synthase and regulatory G. R. Chen J. M. J. T. N. N. J. PubMed Scopus Google Scholar, M. Carling D. F. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, A. D. M. S.C. F. Carling D. Biol. 2000; PubMed Scopus Google Scholar). the that prevented the effects of metformin is that its are by is also consistent with that AMPK regulates the key enzymes that lipid biosynthesis, such as and Seefeld K. Witters L.A. R.A. Biochem. J. 1999; PubMed Scopus Google Scholar, R. F. K. Prentki M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, N. M. A. Eur. J. Biochem. 2004; PubMed Scopus Google Scholar). The that the of metformin in HepG2 cells were completely abrogated by the hepatocellular of insulin resistance for that lipid via In that the effects of metformin on the lipid content of HepG2 cells on activation of the that the by which metformin stimulates AMPK that AMPK is the of the effects of metformin on lipid results also that the effects of metformin on the elevated lipids associated with insulin-resistant states also on an to the by which AMPK regulates lipids as well as to metformin that are of AMPK and lipid and for
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