Advertisement

Hepatic Autophagy Is Suppressed in the Presence of Insulin Resistance and Hyperinsulinemia

INHIBITION OF FoxO1-DEPENDENT EXPRESSION OF KEY AUTOPHAGY GENES BY INSULIN*
  • Hui-Yu Liu
    Footnotes
    Affiliations
    Translational Biology, The Hamner Institutes for Health Sciences, Durham, North Carolina 27709
    Search for articles by this author
  • Jianmin Han
    Footnotes
    Affiliations
    Translational Biology, The Hamner Institutes for Health Sciences, Durham, North Carolina 27709

    Department of Otolaryngology and Head and Neck Surgery, the First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong, China 510080
    Search for articles by this author
  • Sophia Y. Cao
    Affiliations
    Translational Biology, The Hamner Institutes for Health Sciences, Durham, North Carolina 27709
    Search for articles by this author
  • Tao Hong
    Affiliations
    Translational Biology, The Hamner Institutes for Health Sciences, Durham, North Carolina 27709
    Search for articles by this author
  • Degen Zhuo
    Affiliations
    Translational Biology, The Hamner Institutes for Health Sciences, Durham, North Carolina 27709
    Search for articles by this author
  • Jianbo Shi
    Affiliations
    Department of Otolaryngology and Head and Neck Surgery, the First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong, China 510080
    Search for articles by this author
  • Zhenqi Liu
    Affiliations
    Department of Medicine (Endocrinology), University of Virginia Health System, Charlottesville, Virginia 22908
    Search for articles by this author
  • Wenhong Cao
    Correspondence
    To whom correspondence should be addressed: Translational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709.
    Affiliations
    Translational Biology, The Hamner Institutes for Health Sciences, Durham, North Carolina 27709

    Department of Internal Medicine (Endocrinology), Duke University Health System, Durham, North Carolina 27705
    Search for articles by this author
  • Author Footnotes
    * This work was supported, in whole or in part, by National Institutes of Health Grant R01DK076039 (to W. C.). This work was also supported by the Investigator Development Fund from The Hamner Institutes for Health Sciences (to W. C.), American Heart Association Grant SDG-0530244N (to W. C.), and American Diabetes Association Grant 7-09-BS-27 (to W. C.).
    The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.
    1 Both authors contributed equally to this work.
Open AccessPublished:September 16, 2009DOI:https://doi.org/10.1074/jbc.M109.033936
      Autophagy is essential for maintaining both survival and health of cells. Autophagy is normally suppressed by amino acids and insulin. It is unclear what happens to the autophagy activity in the presence of insulin resistance and hyperinsulinemia. In this study, we examined the autophagy activity in the presence of insulin resistance and hyperinsulinemia and the associated mechanism. Insulin resistance and hyperinsulinemia were induced in mice by a high fat diet, followed by measurements of autophagy markers. Our results show that autophagy was suppressed in the livers of mice with insulin resistance and hyperinsulinemia. Transcript levels of some key autophagy genes were also suppressed in the presence of insulin resistance and hyperinsulinemia. Conversely, autophagy activity was increased in the livers of mice with streptozotocin-induced insulin deficiency. Levels of vps34, atg12, and gabarapl1 transcripts were elevated in the livers of mice with insulin deficiency. To study the mechanism, autophagy was induced by nutrient deprivation or glucagon in cultured hepatocytes in the presence or absence of insulin. Autophagy activity and transcript levels of vps34, atg12, and gabarapl1 genes were reduced by insulin. The effect of insulin was largely prevented by overexpression of the constitutive nuclear form of FoxO1. Importantly, autophagy of mitochondria (mitophagy) in cultured cells was suppressed by insulin in the presence of insulin resistance. Together, our results show that autophagy activity and expression of some key autophagy genes were suppressed in the presence of insulin resistance and hyperinsulinemia. Insulin suppression of autophagy involves FoxO1-mediated transcription of key autophagy genes.

      Introduction

      Macroautophagy (autophagy) is a catabolic process whereby long lived large molecules and cellular organelles, such as mitochondria and endoplasmic reticulum (ER),
      The abbreviations used are: ER
      endoplasmic reticulum
      HFD
      high fat diet
      mtROS
      mitochondrion-derived reactive oxygen species
      mtDNA
      mitochondrial DNA
      ND
      normal rodent chow diet
      STZ
      streptozotocin
      GFP
      green fluorescent protein
      EBSS
      Earle's balanced salt solution
      QUICKI
      quantitative insulin sensitivity check index
      HOMA
      homeostasis model assessment
      T1DM
      type1 diabetes mellitus.
      are degraded by lysosomes for an alternative energy source during starvation (
      • Yin X.M.
      • Ding W.X.
      • Gao W.
      ,
      • Levine B.
      • Kroemer G.
      ). Autophagy is normally activated by glucagon or deprivation of amino acids during starvation (
      • Yin X.M.
      • Ding W.X.
      • Gao W.
      ) but inhibited by amino acids and/or insulin through the mTOR- or/and Akt-dependent pathways after food intake (
      • Arsham A.M.
      • Neufeld T.P.
      ,
      • Salih D.A.
      • Brunet A.
      ). Thus, autophagy activity fluctuates with food intakes and fasts. Importantly, autophagy is also essential for maintaining cellular health by removing misfolded large molecules and aged/dysfunctional cellular organelles, such as mitochondria and ER (
      • Yin X.M.
      • Ding W.X.
      • Gao W.
      ,
      • Dröge W.
      • Kinscherf R.
      ). In other words, decreased autophagy will inevitably slow the removal of misfolded large molecules and aged/dysfunctional cellular organelles. Accumulation of these molecules and dysfunctional cellular organelles may not only contribute to the development of cancers (
      • Yin X.M.
      • Ding W.X.
      • Gao W.
      ) but also contribute to the development of metabolic diseases, such as insulin resistance. For example, the accumulation of dysfunctional mitochondria will most likely cause increased mitochondrion-derived oxidative stress, which is known to contribute to the development of insulin resistance (
      • Houstis N.
      • Rosen E.D.
      • Lander E.S.
      ,
      • Pospisilik J.A.
      • Knauf C.
      • Joza N.
      • Benit P.
      • Orthofer M.
      • Cani P.D.
      • Ebersberger I.
      • Nakashima T.
      • Sarao R.
      • Neely G.
      • Esterbauer H.
      • Kozlov A.
      • Kahn C.R.
      • Kroemer G.
      • Rustin P.
      • Burcelin R.
      • Penninger J.M.
      ,
      • Kumashiro N.
      • Tamura Y.
      • Uchida T.
      • Ogihara T.
      • Fujitani Y.
      • Hirose T.
      • Mochizuki H.
      • Kawamori R.
      • Watada H.
      ,
      • Matsuzawa-Nagata N.
      • Takamura T.
      • Ando H.
      • Nakamura S.
      • Kurita S.
      • Misu H.
      • Ota T.
      • Yokoyama M.
      • Honda M.
      • Miyamoto K.
      • Kaneko S.
      ,
      • Liu H.Y.
      • Yehuda-Shnaidman E.
      • Hong T.
      • Han J.
      • Pi J.
      • Liu Z.
      • Cao W.
      ).
      Insulin resistance is either a precursor or a key component of numerous diseases including obesity, metabolic syndrome, T2DM, cardiovascular disorders (including strokes), Alzheimer disease, depression, asthma, chronic inflammatory diseases, cancers, and aging (
      • Accili D.
      ,
      • Burns J.M.
      • Donnelly J.E.
      • Anderson H.S.
      • Mayo M.S.
      • Spencer-Gardner L.
      • Thomas G.
      • Cronk B.B.
      • Haddad Z.
      • Klima D.
      • Hansen D.
      • Brooks W.M.
      ,
      • Cole G.M.
      • Frautschy S.A.
      ,
      • Crowell J.A.
      • Steele V.E.
      • Fay J.R.
      ,
      • Moreira P.I.
      • Santos M.S.
      • Seiça R.
      • Oliveira C.R.
      ,
      • Al-Shawwa B.A.
      • Al-Huniti N.H.
      • DeMattia L.
      • Gershan W.
      ,
      • Sterry W.
      • Strober B.E.
      • Menter A.
      ,
      • Popa C.
      • Netea M.G.
      • van Riel P.L.
      • van der Meer J.W.
      • Stalenhoef A.F.
      ,
      • Okazaki R.
      ). Insulin resistance is primarily caused by the positive energy imbalance between the intake and expenditure of calories. The mechanisms of insulin resistance have been under intense investigation but remain unestablished.
      However, it is known that the induction of insulin resistance in mice by obesity or high fat diet (HFD) is prevented or reversed when production of the mitochondrion-derived reactive oxygen species (mtROS) is blocked (
      • Houstis N.
      • Rosen E.D.
      • Lander E.S.
      ,
      • Pospisilik J.A.
      • Knauf C.
      • Joza N.
      • Benit P.
      • Orthofer M.
      • Cani P.D.
      • Ebersberger I.
      • Nakashima T.
      • Sarao R.
      • Neely G.
      • Esterbauer H.
      • Kozlov A.
      • Kahn C.R.
      • Kroemer G.
      • Rustin P.
      • Burcelin R.
      • Penninger J.M.
      ,
      • Kumashiro N.
      • Tamura Y.
      • Uchida T.
      • Ogihara T.
      • Fujitani Y.
      • Hirose T.
      • Mochizuki H.
      • Kawamori R.
      • Watada H.
      ). Induction of insulin resistance in cultured cells is also blocked when mtROS is scavenged (
      • Houstis N.
      • Rosen E.D.
      • Lander E.S.
      ). It has been clearly shown that oxidative stress is a precursor of insulin resistance (
      • Matsuzawa-Nagata N.
      • Takamura T.
      • Ando H.
      • Nakamura S.
      • Kurita S.
      • Misu H.
      • Ota T.
      • Yokoyama M.
      • Honda M.
      • Miyamoto K.
      • Kaneko S.
      ). Therefore, mtROS plays a critical/necessary role in the development of insulin resistance.
      The level of mtROS production may be influenced by many factors, such as mitochondrial mass and integrity. Much attention has been paid to the production of mitochondria via biogenesis. Numerous studies have shown that mitochondrial mass may be decreased in the subjects with insulin resistance/hyperinsulinemia due to reduced mitochondrial biogenesis. It is well known that decreased mitochondrial number is a cardinal feature of insulin resistance (
      • Petersen K.F.
      • Dufour S.
      • Befroy D.
      • Garcia R.
      • Shulman G.I.
      ,
      • Maassen J.A.
      • ‘T Hart L.M.
      • Van Essen E.
      • Heine R.J.
      • Nijpels G.
      • Jahangir Tafrechi R.S.
      • Raap A.K.
      • Janssen G.M.
      • Lemkes H.H.
      ,
      • Maassen J.A.
      • ‘t Hart L.M.
      • Ouwens D.M.
      ). The ratio between mitochondrion-rich (type I) muscle fibers and glycolytic (type II) muscle fibers is decreased in subjects with insulin resistance (
      • Lillioja S.
      • Young A.A.
      • Culter C.L.
      • Ivy J.L.
      • Abbott W.G.
      • Zawadzki J.K.
      • Yki-Järvinen H.
      • Christin L.
      • Secomb T.W.
      • Bogardus C.
      ,
      • Mårin P.
      • Andersson B.
      • Krotkiewski M.
      • Björntorp P.
      ). Mitochondrial DNA (mtDNA) copy number is decreased in subjects with insulin resistance (
      • Bogacka I.
      • Xie H.
      • Bray G.A.
      • Smith S.R.
      ). Suppression of mitochondrial biogenesis by antiretroviral nucleoside analogues is associated with the development of insulin resistance in patients with AIDS (
      • van der Valk M.
      • Casula M.
      • Weverlingz G.J.
      • van Kuijk K.
      • van Eck-Smit B.
      • Hulsebosch H.J.
      • Nieuwkerk P.
      • van Eeden A.
      • Brinkman K.
      • Lange J.
      • de Ronde A.
      • Reiss P.
      ). We have recently shown that mitochondrial production is decreased by prolonged exposure to insulin, which resembles insulin resistance and hyperinsulinemia (
      • Liu H.Y.
      • Yehuda-Shnaidman E.
      • Hong T.
      • Han J.
      • Pi J.
      • Liu Z.
      • Cao W.
      ,
      • Liu H.Y.
      • Cao S.Y.
      • Hong T.
      • Han J.
      • Liu Z.
      • Cao W.
      ,
      • Liu H.Y.
      • Hong T.
      • Wen G.B.
      • Han J.
      • Zhuo D.
      • Liu Z.
      • Cao W.
      ). However, little attention has been paid to the removal of aged/dysfunctional mitochondria in the presence of insulin resistance and hyperinsulinemia, probably due to the current perception that insulin is not functional in the presence of insulin resistance. Obviously, the removal of aged/dysfunctional mitochondria can affect both the mass and integrity of mitochondria and, hence, influence the production of mtROS. There is no doubt that the removal of mitochondria and other cellular organelles, such as ER, is autophagy-dependent (
      • Yin X.M.
      • Ding W.X.
      • Gao W.
      ,
      • Levine B.
      • Kroemer G.
      ). Thus, in this study, we have examined the level of hepatic autophagy in the presence of insulin resistance/hyperinsulinemia and the associated mechanism.

      DISCUSSION

      Autophagy is not only important for cell survival by providing fuel through the self-digestion of large molecules and cellular organelles but also essential for maintaining cellular health by removing and cleaning up the misfolded molecules and aged/dysfunctional cellular organelles, such as mitochondria and ER (
      • Yin X.M.
      • Ding W.X.
      • Gao W.
      ,
      • Levine B.
      • Kroemer G.
      ). The role of autophagy in prevention of cancers and many other diseases has been extensively investigated (
      • Yin X.M.
      • Ding W.X.
      • Gao W.
      ,
      • Levine B.
      • Kroemer G.
      ). Although autophagy activity is closely connected with nutrients and the central metabolic hormones (insulin and glucagon), the potential role of autophagy in the development of metabolic diseases, such as insulin resistance and its many associated diseases, has hardly been investigated.
      It is well established that autophagy is suppressed by insulin and nutrients when autophagy is not needed for providing fuel during the fed state. In contrast, autophagy is activated during starvation, when plasma levels of nutrients and insulin are low and the plasma glucagon level is high. Thus, the autophagy activity fluctuates with activities of food intake and fast every day. This fluctuation has been established in humans through the evolution for millions of years and become a necessity for cell survival and health. In the presence of insulin resistance/hyperinsulinemia primarily caused by the positive energy imbalance due to overeating and/or physical inactivity, this fluctuation may be lost due to the continuous presence of insulin in the blood. The continuous increase in plasma insulin level can presumably inhibit autophagy continuously. However, the general perception now is that insulin is not functional in the presence of insulin resistance. As a result, some have speculated that autophagy level may be increased in the presence of insulin resistance and hyperinsulinemia (
      • Lenk S.E.
      • Bhat D.
      • Blakeney W.
      • Dunn Jr., W.A.
      ). Results from this study clearly show that the autophagy level (including mitophagy) in the liver is actually decreased by continuous exposure to insulin in animals. The suppressed autophagy will evidently lead to various problems that are associated with the retention of misfolded large molecules and aged/dysfunctional cellular organelles.
      The retention of large molecules due to suppressed autophagy may contribute to the development of many health problems. It is well known that the decreased autophagy is closely associated with the development of various cancers due to the retention of large molecules (
      • Levine B.
      • Kroemer G.
      ). Retention of some large molecules, such as amyloid and Tau proteins, may contribute to the development of Alzheimer disease, which is characterized by intracellular neurofibrillary tangles and extracellular deposits in the form of senile plaques (
      • Bulic B.
      • Pickhardt M.
      • Schmidt B.
      • Mandelkow E.M.
      • Waldmann H.
      • Mandelkow E.
      ,
      • Martinez-Vicente M.
      • Cuervo A.M.
      ,
      • Rubinsztein D.C.
      • Gestwicki J.E.
      • Murphy L.O.
      • Klionsky D.J.
      ,
      • Williams A.
      • Jahreiss L.
      • Sarkar S.
      • Saiki S.
      • Menzies F.M.
      • Ravikumar B.
      • Rubinsztein D.C.
      ). That may be why hyperinsulinemia and insulin resistance is inseparable from Alzheimer disease (
      • Burns J.M.
      • Donnelly J.E.
      • Anderson H.S.
      • Mayo M.S.
      • Spencer-Gardner L.
      • Thomas G.
      • Cronk B.B.
      • Haddad Z.
      • Klima D.
      • Hansen D.
      • Brooks W.M.
      ,
      • Cole G.M.
      • Frautschy S.A.
      ). Retention of large molecules may contribute to the hypertrophy of tissues/organs. For example, retention of myoglobins and other large molecules may lead to the hypertrophy of organs like the heart and smooth muscles. That may be why subjects with insulin resistance/hyperinsulinemia usually have cardiac hypertrophy (
      • Bertrand L.
      • Horman S.
      • Beauloye C.
      • Vanoverschelde J.L.
      ). The thickened vascular wall due to the retention of large molecules may contribute to hypertension, which is a frequent companion of insulin resistance and hyperinsulinemia. Retention of large molecules in the airway may contribute to the thickened airway smooth muscles, render the airway hyper-responsive, and lead to asthma. That may be why subjects with obesity have increased prevalence and severity of asthma (
      • Al-Shawwa B.A.
      • Al-Huniti N.H.
      • DeMattia L.
      • Gershan W.
      ,
      • Thuesen B.H.
      • Husemoen L.L.
      • Hersoug L.G.
      • Pisinger C.
      • Linneberg A.
      ).
      Retention or delayed removal of cellular organelles due to suppressed autophagy may contribute to the development of metabolic diseases. For example, delayed removal of mitochondria (mitophagy) may cause accumulation of aged/dysfunctional mitochondria. It is conceivable that the aged/dysfunctional mitochondria are less efficient in converting the proton gradient into ATP without producing much reactive oxygen species. In other words, the accumulation of aged/dysfunctional mitochondria may contribute to or aggravate the increased oxidative stress in subjects with insulin resistance and hyperinsulinemia. Similarly, the accumulation of aged/dysfunctional ER may cause increased production of misfolded large proteins, such as Tau protein, seen in Alzheimer disease (
      • Bulic B.
      • Pickhardt M.
      • Schmidt B.
      • Mandelkow E.M.
      • Waldmann H.
      • Mandelkow E.
      ) and cause the so-called ER stress. ER stress is known to be associated with insulin resistance and hyperinsulinemia (
      • Tsiotra P.C.
      • Tsigos C.
      ).
      It is known that insulin can suppress autophagy through mTOR (
      • Yin X.M.
      • Ding W.X.
      • Gao W.
      ). mTOR inhibits autophagy via Akt/S6K (
      • Mammucari C.
      • Milan G.
      • Romanello V.
      • Masiero E.
      • Rudolf R.
      • Del Piccolo P.
      • Burden S.J.
      • Di Lisi R.
      • Sandri C.
      • Zhao J.
      • Goldberg A.L.
      • Schiaffino S.
      • Sandri M.
      ). It has recently been shown that insulin can also inhibit autophagy through the Akt/FoxO3 pathway in skeletal muscles (
      • Zhao J.
      • Brault J.J.
      • Schild A.
      • Cao P.
      • Sandri M.
      • Schiaffino S.
      • Lecker S.H.
      • Goldberg A.L.
      ,
      • Mammucari C.
      • Milan G.
      • Romanello V.
      • Masiero E.
      • Rudolf R.
      • Del Piccolo P.
      • Burden S.J.
      • Di Lisi R.
      • Sandri C.
      • Zhao J.
      • Goldberg A.L.
      • Schiaffino S.
      • Sandri M.
      ). Specifically, insulin can inhibit expression of several autophagy genes, which are mediated by FoxO3 (
      • Zhao J.
      • Brault J.J.
      • Schild A.
      • Cao P.
      • Sandri M.
      • Schiaffino S.
      • Lecker S.H.
      • Goldberg A.L.
      ,
      • Mammucari C.
      • Milan G.
      • Romanello V.
      • Masiero E.
      • Rudolf R.
      • Del Piccolo P.
      • Burden S.J.
      • Di Lisi R.
      • Sandri C.
      • Zhao J.
      • Goldberg A.L.
      • Schiaffino S.
      • Sandri M.
      ). In this study, we show that insulin can inhibit autophagy by blocking the expression of vps34, atg12, and gabarapl1 genes. VPS34 is involved in the initiation of autophagy (
      • Yin X.M.
      • Ding W.X.
      • Gao W.
      ). ATG12 is required for the formation of Complex I (see Fig. 2). GEC1 is a part of Complex II (Fig. 2). Our results show that the expression of these genes is FoxO1-dependent in hepatocytes. Thus, our results provide new insight into the mechanism by which insulin suppresses autophagy.
      In summary, results from this study demonstrate that in the presence of insulin resistance and hyperinsulinemia, autophagy is suppressed. The reduced autophagy will lead to delayed removal of misfolded large molecules and aged/dysfunctional cellular organelles. Thus, the reduced autophagy level may be a major contributor to the development of various major diseases that are associated with modern lifestyles characterized by overeating and/or physical inactivity. Our results also shed new light on the mechanism of insulin regulation of autophagy. Therefore, results from this study may provide new approaches for the prevention and treatment of many modern major diseases, such as metabolic syndrome (including insulin resistance), Alzheimer disease, asthma, cancers, and aging.

      REFERENCES

        • Yin X.M.
        • Ding W.X.
        • Gao W.
        Hepatology. 2008; 47: 1773-1785
        • Levine B.
        • Kroemer G.
        Cell. 2008; 132: 27-42
        • Arsham A.M.
        • Neufeld T.P.
        Curr. Opin. Cell Biol. 2006; 18: 589-597
        • Salih D.A.
        • Brunet A.
        Curr. Opin. Cell Biol. 2008; 20: 126-136
        • Dröge W.
        • Kinscherf R.
        Antioxid. Redox Signal. 2008; 10: 661-678
        • Houstis N.
        • Rosen E.D.
        • Lander E.S.
        Nature. 2006; 440: 944-948
        • Pospisilik J.A.
        • Knauf C.
        • Joza N.
        • Benit P.
        • Orthofer M.
        • Cani P.D.
        • Ebersberger I.
        • Nakashima T.
        • Sarao R.
        • Neely G.
        • Esterbauer H.
        • Kozlov A.
        • Kahn C.R.
        • Kroemer G.
        • Rustin P.
        • Burcelin R.
        • Penninger J.M.
        Cell. 2007; 131: 476-491
        • Kumashiro N.
        • Tamura Y.
        • Uchida T.
        • Ogihara T.
        • Fujitani Y.
        • Hirose T.
        • Mochizuki H.
        • Kawamori R.
        • Watada H.
        Diabetes. 2008; 57: 2083-2091
        • Matsuzawa-Nagata N.
        • Takamura T.
        • Ando H.
        • Nakamura S.
        • Kurita S.
        • Misu H.
        • Ota T.
        • Yokoyama M.
        • Honda M.
        • Miyamoto K.
        • Kaneko S.
        Metabolism. 2008; 57: 1071-1077
        • Liu H.Y.
        • Yehuda-Shnaidman E.
        • Hong T.
        • Han J.
        • Pi J.
        • Liu Z.
        • Cao W.
        J. Biol. Chem. 2009; 284: 14087-14095
        • Accili D.
        Diabetes. 2004; 53: 1633-1642
        • Burns J.M.
        • Donnelly J.E.
        • Anderson H.S.
        • Mayo M.S.
        • Spencer-Gardner L.
        • Thomas G.
        • Cronk B.B.
        • Haddad Z.
        • Klima D.
        • Hansen D.
        • Brooks W.M.
        Neurology. 2007; 69: 1094-1104
        • Cole G.M.
        • Frautschy S.A.
        Exp. Gerontol. 2007; 42: 10-21
        • Crowell J.A.
        • Steele V.E.
        • Fay J.R.
        Mol. Cancer Ther. 2007; 6: 2139-2148
        • Moreira P.I.
        • Santos M.S.
        • Seiça R.
        • Oliveira C.R.
        J. Neurol. Sci. 2007; 257: 206-214
        • Al-Shawwa B.A.
        • Al-Huniti N.H.
        • DeMattia L.
        • Gershan W.
        J. Asthma. 2007; 44: 469-473
        • Sterry W.
        • Strober B.E.
        • Menter A.
        Br. J. Dermatol. 2007; 157: 649-655
        • Popa C.
        • Netea M.G.
        • van Riel P.L.
        • van der Meer J.W.
        • Stalenhoef A.F.
        J. Lipid Res. 2007; 48: 751-762
        • Okazaki R.
        Clin. Calcium. 2008; 18: 638-643
        • Petersen K.F.
        • Dufour S.
        • Befroy D.
        • Garcia R.
        • Shulman G.I.
        N. Engl. J. Med. 2004; 350: 664-671
        • Maassen J.A.
        • ‘T Hart L.M.
        • Van Essen E.
        • Heine R.J.
        • Nijpels G.
        • Jahangir Tafrechi R.S.
        • Raap A.K.
        • Janssen G.M.
        • Lemkes H.H.
        Diabetes. 2004; 53: S103-S109
        • Maassen J.A.
        • ‘t Hart L.M.
        • Ouwens D.M.
        Curr. Opin. Clin. Nutr. Metab. Care. 2007; 10: 693-697
        • Lillioja S.
        • Young A.A.
        • Culter C.L.
        • Ivy J.L.
        • Abbott W.G.
        • Zawadzki J.K.
        • Yki-Järvinen H.
        • Christin L.
        • Secomb T.W.
        • Bogardus C.
        J. Clin. Invest. 1987; 80: 415-424
        • Mårin P.
        • Andersson B.
        • Krotkiewski M.
        • Björntorp P.
        Diabetes Care. 1994; 17: 382-386
        • Bogacka I.
        • Xie H.
        • Bray G.A.
        • Smith S.R.
        Diabetes. 2005; 54: 1392-1399
        • van der Valk M.
        • Casula M.
        • Weverlingz G.J.
        • van Kuijk K.
        • van Eck-Smit B.
        • Hulsebosch H.J.
        • Nieuwkerk P.
        • van Eeden A.
        • Brinkman K.
        • Lange J.
        • de Ronde A.
        • Reiss P.
        Antivir. Ther. 2004; 9: 385-393
        • Liu H.Y.
        • Cao S.Y.
        • Hong T.
        • Han J.
        • Liu Z.
        • Cao W.
        J. Biol. Chem. 2009; 284 (9 16): 27090-27100
        • Liu H.Y.
        • Hong T.
        • Wen G.B.
        • Han J.
        • Zhuo D.
        • Liu Z.
        • Cao W.
        Am. J. Physiol. Endocrinol Metab. 2009; 297: E898-E906
        • Cao W.
        • Collins Q.F.
        • Becker T.C.
        • Robidoux J.
        • Lupo Jr., E.G.
        • Xiong Y.
        • Daniel K.W.
        • Floering L.
        • Collins S.
        J. Biol. Chem. 2005; 280: 42731-42737
        • Xiong Y.
        • Collins Q.F.
        • An J.
        • Lupo Jr., E.
        • Liu H.Y.
        • Liu D.
        • Robidoux J.
        • Liu Z
        • Cao W.
        J. Biol. Chem. 2007; 282: 4975-4982
        • Collins Q.F.
        • Xiong Y.
        • Lupo Jr., E.G.
        • Liu H.Y.
        • Cao W.
        J. Biol. Chem. 2006; 281: 24336-24344
        • Collins Q.F.
        • Liu H.Y.
        • Pi J.
        • Liu Z.
        • Quon M.J.
        • Cao W.
        J. Biol. Chem. 2007; 282: 30143-30149
        • Liu H.Y.
        • Collins Q.F.
        • Xiong Y.
        • Moukdar F.
        • Lupo Jr., E.G.
        • Liu Z.
        • Cao W.
        J. Biol. Chem. 2007; 282: 14205-14212
        • Liu H.Y.
        • Collins Q.F.
        • Moukdar F.
        • Zhuo D.
        • Han J.
        • Hong T.
        • Collins S.
        • Cao W.
        J. Biol. Chem. 2008; 283: 12056-12063
        • Liu H.Y.
        • Wen G.B.
        • Han J.
        • Hong T.
        • Zhuo D.
        • Liu Z.
        • Cao W.
        J. Biol. Chem. 2008; 283: 30642-30649
        • Lee S.
        • Muniyappa R.
        • Yan X.
        • Chen H.
        • Yue L.Q.
        • Hong E.G.
        • Kim J.K.
        • Quon M.J.
        Am. J. Physiol. Endocrinol. Metab. 2008; 294: E261-E270
        • Tallóczy Z.
        • Jiang W.
        • Virgin 4th, H.W.
        • Leib D.A.
        • Scheuner D.
        • Kaufman R.J.
        • Eskelinen E.L.
        • Levine B.
        Proc. Natl. Acad. Sci. U.S.A. 2002; 99: 190-195
        • Meijer A.J.
        • Codogno P.
        Autophagy. 2007; 3: 523-526
        • Saitoh T.
        • Fujita N.
        • Jang M.H.
        • Uematsu S.
        • Yang B.G.
        • Satoh T.
        • Omori H.
        • Noda T.
        • Yamamoto N.
        • Komatsu M.
        • Tanaka K.
        • Kawai T.
        • Tsujimura T.
        • Takeuchi O.
        • Yoshimori T.
        • Akira S.
        Nature. 2008; 456: 264-268
        • Ebato C.
        • Uchida T.
        • Arakawa M.
        • Komatsu M.
        • Ueno T.
        • Komiya K.
        • Azuma K.
        • Hirose T.
        • Tanaka K.
        • Kominami E.
        • Kawamori R.
        • Fujitani Y.
        • Watada H.
        Cell Metab. 2008; 8: 325-332
        • Zhao J.
        • Brault J.J.
        • Schild A.
        • Cao P.
        • Sandri M.
        • Schiaffino S.
        • Lecker S.H.
        • Goldberg A.L.
        Cell Metab. 2007; 6: 472-483
        • Lenk S.E.
        • Bhat D.
        • Blakeney W.
        • Dunn Jr., W.A.
        Am. J. Physiol. 1992; 263: E856-E862
        • Bulic B.
        • Pickhardt M.
        • Schmidt B.
        • Mandelkow E.M.
        • Waldmann H.
        • Mandelkow E.
        Angew Chem. Int. Ed. Engl. 2009; 48: 1740-1752
        • Martinez-Vicente M.
        • Cuervo A.M.
        Lancet Neurol. 2007; 6: 352-361
        • Rubinsztein D.C.
        • Gestwicki J.E.
        • Murphy L.O.
        • Klionsky D.J.
        Nat. Rev. Drug Discov. 2007; 6: 304-312
        • Williams A.
        • Jahreiss L.
        • Sarkar S.
        • Saiki S.
        • Menzies F.M.
        • Ravikumar B.
        • Rubinsztein D.C.
        Curr. Top. Dev. Biol. 2006; 76: 89-101
        • Bertrand L.
        • Horman S.
        • Beauloye C.
        • Vanoverschelde J.L.
        Cardiovasc. Res. 2008; 79: 238-248
        • Thuesen B.H.
        • Husemoen L.L.
        • Hersoug L.G.
        • Pisinger C.
        • Linneberg A.
        Clin. Exp. Allergy. 2009; 39: 700-707
        • Tsiotra P.C.
        • Tsigos C.
        Ann. N.Y. Acad. Sci. 2006; 1083: 63-76
        • Mammucari C.
        • Milan G.
        • Romanello V.
        • Masiero E.
        • Rudolf R.
        • Del Piccolo P.
        • Burden S.J.
        • Di Lisi R.
        • Sandri C.
        • Zhao J.
        • Goldberg A.L.
        • Schiaffino S.
        • Sandri M.
        Cell Metab. 2007; 6: 458-471