Metabolic Disorders and Cancer: Hepatocyte Store-Operated Ca2+ Channels in Nonalcoholic Fatty Liver Disease

  • Eunüs S. Ali
  • Grigori Y. Rychkov
  • Greg J. BarrittEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 993)


In steatotic hepatocytes, intracellular Ca2+ homeostasis is substantially altered compared to normal. Decreased Ca2+ in the endoplasmic reticulum (ER) can lead to ER stress, an important mediator of the progression of liver steatosis to nonalcoholic steatohepatitis, type 2 diabetes, and hepatocellular carcinoma. Store-operated Ca2+ channels (SOCs) in hepatocytes are composed principally of Orai1 and STIM1 proteins. Their main role is the maintenance of adequate Ca2+ in the lumen of the ER. In steatotic hepatocytes, store-operated Ca2+ entry (SOCE) is substantially inhibited. This inhibition is associated with a decrease in Ca2+ in the ER. Lipid-induced inhibition of SOCE is mediated by protein kinase C (PKC) and may involve the phosphorylation and subsequent inhibition of Orai1. Experimental inhibition of SOCE enhances lipid accumulation in normal hepatocytes incubated in the presence of exogenous fatty acids. The antidiabetic drug exendin-4 reverses the lipid-induced inhibition of SOCE and decreases liver lipid with rapid onset. It is proposed that lipid-induced inhibition of SOCE in the plasma membrane and of SERCA2b in the ER membrane leads to a persistent decrease in ER Ca2+, ER stress, and the ER stress response, which in turn enhances (amplifies) lipid accumulation. A low level of persistent SOCE due to chronic ER Ca2+ depletion in steatotic hepatocytes may contribute to an elevated cytoplasmic-free Ca2+ concentration leading to the activation of calcium-calmodulin kinase II (CaMKII), decreased lipid removal by autophagy, and insulin resistance. It is concluded that lipid-induced inhibition of SOCE plays an important role in the progression of liver steatosis to insulin insensitivity and hepatocellular carcinoma.


Store-operated Ca2+ entry Liver Steatosis Exendin-4 GLP-1 Intracellular Ca2+ Cyclic AMP 



This research was supported by the Diabetes Australia Research Trust (grant number Y11-BARG); the Rebecca L. Cooper Medical Research Foundation and the Flinders Medical Centre Foundation.


  1. Ali ES, Hua J, Wilson CH, Tallis GA, Zhou FH, Rychkov GY, Barritt GJ (2016) The glucagon-like peptide-1 analogue exendin-4 reverses impaired intracellular Ca2+ signalling in steatotic hepatocytes. Biochim Biophys Acta 1863(9):2135–2146PubMedCrossRefGoogle Scholar
  2. Aromataris EC, Roberts ML, Barritt GJ, Rychkov GY (2006) Glucagon activates Ca2+ and Cl- channels in rat hepatocytes. J Physiol (Lond) 573(Pt 3):611–625CrossRefGoogle Scholar
  3. Aromataris EC, Castro J, Rychkov G, Barritt GJ (2008) Store-operated Ca2+ channels and Stromal Interaction Molecule 1 (STIM1) are targets for the actions of bile acids on liver cells. Biochim Biophys Acta 1783:874–885PubMedCrossRefGoogle Scholar
  4. Arruda AP, Hotamisligil GS (2015) Calcium homeostasis and organelle function in the pathogenesis of obesity and diabetes. Cell Metab 22(3):381–397PubMedPubMedCentralCrossRefGoogle Scholar
  5. Arruda AP, Pers BM, Parlakgul G, Guney E, Inouye K, Hotamisligil GS (2014) Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity. Nat Med 20(12):1427–1435PubMedPubMedCentralCrossRefGoogle Scholar
  6. Auld A, Chen J, Brereton HM, Wang YJ, Gregory RB, Barritt GJ (2000) Store-operated Ca(2+) inflow in Reuber hepatoma cells is inhibited by voltage-operated Ca(2+) channel antagonists and, in contrast to freshly isolated hepatocytes, does not require a pertussis toxin-sensitive trimeric GTP-binding protein. Biochim Biophys Acta 1497(1):11–26PubMedCrossRefGoogle Scholar
  7. Barritt GJ (1999) Does a decrease in subplasmalemmal Ca2+ explain how store-operated Ca2+ channels are opened? Cell Calcium 23(1):65–75CrossRefGoogle Scholar
  8. Barritt GJ, Chen J, Rychkov GY (2008) Ca(2+)-permeable channels in the hepatocyte plasma membrane and their roles in hepatocyte physiology. Biochim Biophys Acta 1783(5):651–672PubMedCrossRefGoogle Scholar
  9. Bartlett PJ, Gaspers LD, Pierobon N, Thomas AP (2014) Calcium-dependent regulation of glucose homeostasis in the liver. Cell Calcium 55(6):306–316PubMedCrossRefGoogle Scholar
  10. Bataller R, Gasull X, Gines P, Hellemans K, Görbig MN, Nicolas JM, Sancho-Bru P, De Las Heras D, Gual A, Geerts A, Arroyo V, Rodes J (2001) In vitro and in vivo activation of rat hepatic stellate cells results in de novo expression of L-type voltage-operated calcium channels. Hepatology 33(4):956–962PubMedCrossRefGoogle Scholar
  11. Baumbach J, Hummel P, Bickmeyer I, Kowalczyk KM, Frank M, Knorr K, Hildebrandt A, Riedel D, Jäckle H, Kühnlein RP (2014) A Drosophila in vivo screen identifies store-operated calcium entry as a key regulator of adiposity. Cell Metab 19(2):331–343PubMedCrossRefGoogle Scholar
  12. Beebe SJ, Koch SR, Chu DT, Corbin JD, Granner DK (1987) Regulation of phosphoenolpyruvate carboxykinase gene transcription in H4IIE hepatoma cells: evidence for a primary role of the catalytic subunit of 3′,5′-cyclic adenosine monophosphate-dependent protein kinase. Mol Endocrinol 1(9):639–647PubMedCrossRefGoogle Scholar
  13. Boyer JL (2002) Bile formation and cholestasis Schiffs diseases of the liver, vol 1, 9th edn. Lippincott, Williams & Wilkins, Philadelphia, pp 135–165Google Scholar
  14. Bozaykut P, Sahin A, Karademir B, Ozer NK (2016) Endoplasmic reticulum stress related molecular mechanisms in nonalcoholic steatohepatitis. Mech Ageing Dev 157:17–29PubMedCrossRefGoogle Scholar
  15. Brereton HM, Harland ML, Froscio M, Petronijevic T, Barritt GJ (1997) Novel variants of voltage-operated calcium channel alpha 1-subunit transcripts in a rat liver-derived cell line: deletion in the IVS4 voltage sensing region. Cell Calcium 22(1):39–52PubMedCrossRefGoogle Scholar
  16. Burgess GM, Godfrey PP, McKinney JS, Berridge MJ, Irvine RF, Putney JW Jr (1984) The second messenger linking receptor activation to internal Ca release in liver. Nature 309(5963):63–66PubMedCrossRefGoogle Scholar
  17. Cabre N, Camps J, Joven J (2016) Inflammation, mitochondrial metabolism and nutrition: the multi-faceted progression of non-alcoholic fatty liver disease to hepatocellular carcinoma. Hepatobiliary Surg Nutr 5(5):438–443PubMedPubMedCentralCrossRefGoogle Scholar
  18. Campbell JE, Drucker DJ (2013) Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 17(6):819–837PubMedCrossRefGoogle Scholar
  19. Cantley JL, Yoshimura T, Camporez JP, Zhang D, Jornayvaz FR, Kumashiro N, Guebre-Egziabher F, Jurczak MJ, Kahn M, Guigni BA, Serr J, Hankin J, Murphy RC, Cline GW, Bhanot S, Manchem VP, Brown JM, Samuel VT, Shulman GI (2013) CGI-58 knockdown sequesters diacylglycerols in lipid droplets/ER-preventing diacylglycerol-mediated hepatic insulin resistance. Proc Natl Acad Sci U S A 110(5):1869–1874PubMedPubMedCentralCrossRefGoogle Scholar
  20. Carrasco S, Meyer T (2011) STIM proteins and the endoplasmic reticulum-plasma membrane junctions. Annu Rev Biochem 80:973–1000PubMedPubMedCentralCrossRefGoogle Scholar
  21. Castro J, Aromataris EC, Rychkov GY, Barritt GJ (2009) A small component of the endoplasmic reticulum is required for store-operated Ca2+ channel activation in liver cells: evidence from studies using TRPV1 and taurodeoxycholic acid. Biochem J 418(3):553–566PubMedCrossRefGoogle Scholar
  22. Chan C, Harland ML, Webb SE, Chen J, Miller AL, Barritt GJ (2004) Evaluation, using targeted aequorins, of the roles of the endoplasmic reticulum and its (Ca2++Mg2+)ATP-ases in the activation of store-operated Ca2+ channels in liver cells. Cell Calcium 35(4):317–331PubMedCrossRefGoogle Scholar
  23. Chiono M, Mahey R, Tate G, Cooper DM (1995) Capacitative Ca2+ entry exclusively inhibits cAMP synthesis in C6-2B glioma cells. Evidence that physiologically evoked Ca2+ entry regulates Ca(2+)-inhibitable adenylyl cyclase in non-excitable cells. J Biol Chem 270(3):1149–1155PubMedCrossRefGoogle Scholar
  24. Cooper DM (2015) Store-operated Ca(2)(+)-entry and adenylyl cyclase. Cell Calcium 58(4):368–375PubMedCrossRefGoogle Scholar
  25. Courjaret R, Machaca K (2014) Mid-range Ca2+ signalling mediated by functional coupling between store-operated Ca2+ entry and IP3-dependent Ca2+ release. Nat Commun 5:3916PubMedCrossRefGoogle Scholar
  26. Crane J, McGowan B (2016) The GLP-1 agonist, liraglutide, as a pharmacotherapy for obesity. Ther Adv Chronic Dis 7(2):92–107PubMedCrossRefGoogle Scholar
  27. Dagli ML, Guerra JL, Sinhorini IL, Wu TS, Rizzi MB, Penteado MV, Moreno FS (1998) Beta-carotene reduces the ductular (oval) cell reaction in the liver of Wistar rats submitted to the resistant hepatocyte model of carcinogenesis. Pathology 30(3):259–266PubMedCrossRefGoogle Scholar
  28. Dara L, Ji C, Kaplowitz N (2011) The contribution of endoplasmic reticulum stress to liver diseases. Hepatology 53(5):1752–1763PubMedPubMedCentralCrossRefGoogle Scholar
  29. Derler I, Jardin I, Romanin C (2016a) Molecular mechanisms of STIM/Orai communication. Am J Physiol Cell Physiol 310(8):C643–C662PubMedPubMedCentralGoogle Scholar
  30. Derler I, Jardin I, Stathopulos PB, Muik M, Fahrner M, Zayats V, Pandey SK, Poteser M, Lackner B, Absolonova M, Schindl R, Groschner K, Ettrich R, Ikura M, Romanin C (2016b) Cholesterol modulates Orai1 channel function. Sci Signal 9(412):ra10PubMedPubMedCentralCrossRefGoogle Scholar
  31. Dong H, Czaja MJ (2011) Regulation of lipid droplets by autophagy. Trends Endocrinol Metab 22(6):234–240PubMedPubMedCentralCrossRefGoogle Scholar
  32. Egnatchik RA, Leamy AK, Jacobson DA, Shiota M, Young JD (2014) ER calcium release promotes mitochondrial dysfunction and hepatic cell lipotoxicity in response to palmitate overload. Mol Metab 3(5):544–553PubMedPubMedCentralCrossRefGoogle Scholar
  33. El Boustany C, Bidaux G, Enfissi A, Delcourt P, Prevarskaya N, Capiod T (2008) Capacitative calcium entry and transient receptor potential canonical 6 expression control human hepatoma cell proliferation. Hepatology 47(6):2068–2077PubMedCrossRefGoogle Scholar
  34. Engin F, Hotamisligil GS (2010) Restoring endoplasmic reticulum function by chemical chaperones: an emerging therapeutic approach for metabolic diseases. Diabetes Obes Metab 12(Suppl 2):108–115PubMedCrossRefGoogle Scholar
  35. Exton JH, Blackmore PF, El-Refai MF, Dehaye JP, Strickland WG, Cherrington AD, Chan TM, Assimacopoulos-Jeannet FD, Chrisman TD (1981) Mechanisms of hormonal regulation of liver metabolism. Adv Cyclic Nucleotide Res 14:491–505PubMedGoogle Scholar
  36. Fahrner M, Derler I, Jardin I, Romanin C (2013) The STIM1/Orai signaling machinery. Channels 7(5):330–343PubMedPubMedCentralCrossRefGoogle Scholar
  37. Fernando KC, Gregory RB, Barritt GJ (1998) Protein kinase A regulates the disposition of Ca2+ which enters the cytoplasmic space through store-activated Ca2+ channels in rat hepatocytes by diverting inflowing Ca2+ to mitochondria. Biochem J 330(Pt 3):1179–1187PubMedPubMedCentralCrossRefGoogle Scholar
  38. Font-Burgada J, Sun B, Karin M (2016) Obesity and cancer: the oil that feeds the flame. Cell Metab 23(1):48–62PubMedCrossRefGoogle Scholar
  39. Fu S, Yang L, Li P, Hofmann O, Dicker L, Hide W, Lin X, Watkins SM, Ivanov AR, Hotamisligil GS (2011) Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 473(7348):528–531PubMedPubMedCentralCrossRefGoogle Scholar
  40. Fu S, Watkins SM, Hotamisligil GS (2012) The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab 15(5):623–634PubMedCrossRefGoogle Scholar
  41. Gao J, Zhang Y, Yu C, Tan F, Wang L (2016) Spontaneous nonalcoholic fatty liver disease and ER stress in Sidt2 deficiency mice. Biochem Biophys Res Commun 475(4):326–332CrossRefGoogle Scholar
  42. Gaspers LD, Thomas AP (2005) Calcium signaling in liver. Cell Calcium 38(3–4):329–342PubMedCrossRefGoogle Scholar
  43. Golovina VA (2005) Visualization of localized store-operated calcium entry in mouse astrocytes. Close proximity to the endoplasmic reticulum. J Physiol (Lond) 564(Pt 3):737–749CrossRefGoogle Scholar
  44. Graf J, Häussinger D (1996) Ion transport in hepatocytes: mechanisms and correlations to cell volume, hormone actions and metabolism. J Hepatol 24(Suppl 1):53–77PubMedGoogle Scholar
  45. Greene MW, Burrington CM, Ruhoff MS, Johnson AK, Chongkrairatanakul T, Kangwanpornsiri A (2010) PKC{delta} is activated in a dietary model of steatohepatitis and regulates endoplasmic reticulum stress and cell death. J Biol Chem 285(53):42115–42129PubMedPubMedCentralCrossRefGoogle Scholar
  46. Gregory RB, Wilcox RA, Berven LA, van Straten NC, van der Marel GA, van Boom JH, Barritt GJ (1999) Evidence for the involvement of a small subregion of the endoplasmic reticulum in the inositol trisphosphate receptor-induced activation of Ca2+ inflow in rat hepatocytes. Biochem J 341(Pt 2):401–408PubMedPubMedCentralCrossRefGoogle Scholar
  47. Han J, Kaufman RJ (2016) The role of ER stress in lipid metabolism and lipotoxicity. J Lipid Res 57(8):329–338CrossRefGoogle Scholar
  48. Hijioka T, Rosenberg RL, Lemasters JJ, Thurman RG (1992) Kupffer cells contain voltage-dependent calcium channels. Mol Pharmacol 41(3):435–440PubMedGoogle Scholar
  49. Holowka D, Korzeniowski MK, Bryant KL, Baird B (2014) Polyunsaturated fatty acids inhibit stimulated coupling between the ER Ca(2+) sensor STIM1 and the Ca(2+) channel protein Orai1 in a process that correlates with inhibition of stimulated STIM1 oligomerization. Biochim Biophys Acta 1841(8):1210–1216PubMedPubMedCentralCrossRefGoogle Scholar
  50. Huang W, Bansode R, Mehta M, Mehta KD (2009) Loss of protein kinase Cbeta function protects mice against diet-induced obesity and development of hepatic steatosis and insulin resistance. Hepatology 49(5):1525–1536PubMedPubMedCentralCrossRefGoogle Scholar
  51. Hughes BP, Milton SE, Barritt GJ, Auld AM (1986) Studies with verapamil and nifedipine provide evidence for the presence in the liver cell plasma membrane of two types of Ca2+ inflow transporter which are dissimilar to potential-operated Ca2+ channels. Biochem Pharmacol 35(18):3045–3052PubMedCrossRefGoogle Scholar
  52. Jones BF, Boyles RR, Hwang SY, Bird GS, Putney JW Jr (2008) Calcium influx mechanisms underlying calcium oscillations in rat hepatocytes. Hepatology 48(4):1273–1281PubMedPubMedCentralCrossRefGoogle Scholar
  53. Jornayvaz FR, Shulman GI (2012) Diacylglycerol activation of protein kinase Ce and hepatic insulin resistance. Cell Metab 15:574–584PubMedPubMedCentralCrossRefGoogle Scholar
  54. Jornayvaz FR, Birkenfeld AL, Jurczak MJ, Kanda S, Guigni BA, Jiang DC, Zhang D, Lee HY, Samuel VT, Shulman GI (2011) Hepatic insulin resistance in mice with hepatic overexpression of diacylglycerol acyltransferase 2. Proc Natl Acad Sci U S A 108(14):5748–5752PubMedPubMedCentralCrossRefGoogle Scholar
  55. Jousset H, Frieden M, Demaurex N (2007) STIM1 knockdown reveals that store-operated Ca2+ channels located close to sarco/endoplasmic Ca2+ ATPases (SERCA) pumps silently refill the endoplasmic reticulum. J Biol Chem 282(15):11456–11464PubMedCrossRefGoogle Scholar
  56. Kammoun HL, Chabanon H, Hainault I, Luquet S, Magnan C, Koike T, Ferré P, Foufelle F (2009) GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J Clin Invest 119(5):1201–1215PubMedPubMedCentralCrossRefGoogle Scholar
  57. Kang S, Dahl R, Hsieh W, Shin A, Zsebo KM, Buettner C, Hajjar RJ, Lebeche D (2016) Small molecular allosteric activator of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) attenuates diabetes and metabolic disorders. J Biol Chem 291(10):5185–5198PubMedCrossRefGoogle Scholar
  58. Karin M, Dhar D (2016) Liver carcinogenesis: from naughty chemicals to soothing fat and the surprising role of NRF2. Carcinogenesis 37(6):541–546PubMedPubMedCentralCrossRefGoogle Scholar
  59. Kars M, Yang L, Gregor MF, Mohammed BS, Pietka TA, Finck BN, Patterson BW, Horton JD, Mittendorfer B, Hotamisligil GS, Klein S (2010) Tauroursodeoxycholic Acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes 59(8):1899–1905PubMedPubMedCentralCrossRefGoogle Scholar
  60. Kawasaki T, Ueyama T, Lange I, Feske S, Saito N (2010) Protein kinase C-induced phosphorylation of Orai1 regulates the intracellular Ca2+ level via the store-operated Ca2+ channel. J Biol Chem 285(33):25720–25730PubMedPubMedCentralCrossRefGoogle Scholar
  61. Khera R, Murad MH, Chandar AK, Dulai PS, Wang Z, Prokop LJ, Loomba R, Camilleri M, Singh S (2016) Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis. JAMA 315(22):2424–2434PubMedCrossRefGoogle Scholar
  62. Kheradpezhouh E, Ma L, Morphett A, Barritt GJ, Rychkov GY (2014) TRPM2 channels mediate acetaminophen-induced liver damage. Proc Natl Acad Sci U S A 111(8):3176–3181PubMedPubMedCentralCrossRefGoogle Scholar
  63. Kim S (2016) Drugs to treat obesity: do they work? Postgrad Med J 92(1089):401–406PubMedCrossRefGoogle Scholar
  64. Lau JK, Zhang X, Yu J (2016) Animal models of non-alcoholic fatty liver disease: current perspectives and recent advances. J Pathol 241(1):36–44PubMedPubMedCentralCrossRefGoogle Scholar
  65. Lee J, Hong SW, Chae SW, Kim DH, Choi JH, Bae JC, Park SE, Rhee EJ, Park CY, Oh KW, Park SW, Kim SW, Lee WY (2012) Exendin-4 improves steatohepatitis by increasing Sirt1 expression in high-fat diet-induced obese C57BL/6J mice. PLoS One 7(2):e31394PubMedPubMedCentralCrossRefGoogle Scholar
  66. Lee J, Hong SW, Park SE, Rhee EJ, Park CY, Oh KW, Park SW, Lee WY (2014) Exendin-4 regulates lipid metabolism and fibroblast growth factor 21 in hepatic steatosis. Metabolism 63(8):1041–1048PubMedCrossRefGoogle Scholar
  67. Leite MF, Nathanson MH (2001) The liver biology and pathobiology. Lippincott, Williams and Wilkins, Philadelphia, pp 537–554Google Scholar
  68. Litjens T, Nguyen T, Castro J, Aromataris EC, Jones L, Barritt GJ, Rychkov GY (2007) Phospholipase C-gamma1 is required for the activation of store-operated Ca2+ channels in liver cells. Biochem J 405(2):269–276PubMedPubMedCentralCrossRefGoogle Scholar
  69. Liu K, Czaja MJ (2013) Regulation of lipid stores and metabolism by lipophagy. Cell Death Differ 20(1):3–11PubMedCrossRefGoogle Scholar
  70. Liu W, Baker RD, Bhatia T, Zhu L, Baker SS (2016) Pathogenesis of nonalcoholic steatohepatitis. Cell Mol Life Sci 73(10):1969–1987PubMedCrossRefGoogle Scholar
  71. Lobeck I, Donnelly B, Dupree P, Mahe MM, McNeal M, Mohanty SK, Tiao G (2016) Rhesus rotavirus VP6 regulates ERK-dependent calcium influx in cholangiocytes. Virology 499:185–195PubMedCrossRefGoogle Scholar
  72. Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, Stroncek DF, Terabe M, Kapoor V, ElGindi M, Han M, Thornton AM, Zhang H, Egger M, Luo J, Felsher DW, McVicar DW, Weber A, Heikenwalder M, Greten TF (2016) NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nat Med 531(7593):253–257Google Scholar
  73. Manjarres IM, Alonso MT, Garcia-Sancho J (2011) Calcium entry-calcium refilling (CECR) coupling between store-operated Ca(2+) entry and sarco/endoplasmic reticulum Ca(2+)-ATPase. Cell Calcium 49(3):153–161PubMedCrossRefGoogle Scholar
  74. Martinez-Lopez N, Singh R (2015) Autophagy and lipid droplets in the liver. Annu Rev Nutr 35:215–237PubMedCrossRefGoogle Scholar
  75. Mashek DG, Khan SA, Sathyanarayan A, Ploeger JM, Franklin MP (2015) Hepatic lipid droplet biology: getting to the root of fatty liver. Hepatology 62(3):964–967PubMedPubMedCentralCrossRefGoogle Scholar
  76. Maus M, Cuk M, Patel B, Lian J, Ouimet M, Kaufmann U, Yang J, Horvath R, Hornig-Do HT, Chrzanowska-Lightowlers ZM, Moore KJ, Cuervo AM, Feske S (2017) Store-operated Ca2+ entry controls induction of lipolysis and the transcriptional reprogramming to lipid metabolism. Cell Metab 25(3):698–712PubMedCrossRefGoogle Scholar
  77. Mekahli D, Bultynck G, Parys JB, De Smedt H, Missiaen L (2011) Endoplasmic-reticulum calcium depletion and disease. Cold Spring Harb Perspect Biol 3(6):a004317PubMedPubMedCentralCrossRefGoogle Scholar
  78. Musso G, Cassader M, Gambino R (2016) Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies. Nat Rev Drug Discov 15(4):249–274PubMedCrossRefGoogle Scholar
  79. Nakamura S, Takamura T, Matsuzawa-Nagata N, Takayama H, Misu H, Noda H, Nabemoto S, Kurita S, Ota T, Ando H, Miyamoto K, Kaneko S (2009) Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria. J Biol Chem 284(22):14809–14818PubMedPubMedCentralCrossRefGoogle Scholar
  80. Nyenwe EA, Jerkins TW, Umpierrez GE, Kitabchi AE (2011) Management of type 2 diabetes: evolving strategies for the treatment of patients with type 2 diabetes. Metabolism 60(1):1–23PubMedPubMedCentralCrossRefGoogle Scholar
  81. Ozcan L, Tabas I (2016) Calcium signalling and ER stress in insulin resistance and atherosclerosis. J Intern Med 280(5):457–464PubMedPubMedCentralCrossRefGoogle Scholar
  82. Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Görgün CZ, Hotamisligil GS (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313(5790):1137–1140PubMedPubMedCentralCrossRefGoogle Scholar
  83. Ozcan L, Wong CC, Li G, Xu T, Pajvani U, Park SK, Wronska A, Chen BX, Marks AR, Fukamizu A, Backs J, Singer HA, Yates JR 3rd, Accili D, Tabas I (2012) Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity. Cell Metab 15:739–751PubMedPubMedCentralCrossRefGoogle Scholar
  84. Ozcan L, Cristina de Souza J, Harari AA, Backs J, Olson EN, Tabas I (2013) Activation of calcium/calmodulin-dependent protein kinase II in obesity mediates suppression of hepatic insulin signaling. Cell Metab 18(6):803–815PubMedCrossRefGoogle Scholar
  85. Pagliassotti MJ, Kim PY, Estrada AL, Stewart CM, Gentile CL (2016) Endoplasmic reticulum stress in obesity and obesity-related disorders: an expanded view. Metabolism 65:1238–1246PubMedPubMedCentralCrossRefGoogle Scholar
  86. Parekh AB (2011) Decoding cytosolic Ca2+ oscillations. Trends Biochem Sci 36(2):78–87PubMedCrossRefGoogle Scholar
  87. Park HW, Lee JH (2014) Calcium channel blockers as potential therapeutics for obesity-associated autophagy defects and fatty liver pathologies. Autophagy 10(12):2385–2386PubMedCrossRefGoogle Scholar
  88. Park SW, Zhou Y, Lee J, Ozcan U (2010) Sarco(endo)plasmic reticulum Ca2+-ATPase 2b is a major regulator of endoplasmic reticulum stress and glucose homeostasis in obesity. Proc Natl Acad Sci U S A 107(45):19320–19325PubMedPubMedCentralCrossRefGoogle Scholar
  89. Park HW, Park H, Semple IA, Jang I, Ro SH, Kim M, Cazares VA, Stuenkel EL, Kim JJ, Kim JS, Lee JH (2014) Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers. Nat Commun 5:4834PubMedPubMedCentralCrossRefGoogle Scholar
  90. Perry RJ, Samuel VT, Petersen KF, Shulman GI (2014) The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 510(7503):84–91PubMedPubMedCentralCrossRefGoogle Scholar
  91. Pinzani M, Failli P, Ruocco C, Casini A, Milani S, Baldi E, Giotti A, Gentilini P (1992) Fat-storing cells as liver-specific pericytes. Spatial dynamics of agonist-stimulated intracellular calcium transients. J Clin Invest 90(2):642–646PubMedPubMedCentralCrossRefGoogle Scholar
  92. Prakriya M, Lewis RS (2015) Store-operated calcium channels. Physiol Rev 95(4):1383–1436PubMedPubMedCentralCrossRefGoogle Scholar
  93. Puljak L, Pagliassotti MJ, Wei Y, Qadri I, Parameswara V, Esser V, Fitz JG, Kilic G (2005) Inhibition of cellular responses to insulin in a rat liver cell line. A role for PKC in insulin resistance. J Physiol 563(Pt 2):471–482PubMedPubMedCentralCrossRefGoogle Scholar
  94. Rieusset J (2017) Endoplasmic reticulum-mitochondria calcium signalling in hepatic metabolic diseases. Biochim Biophys Acta pii:S0167-4889(17)30003-4. doi: 10.1016/j.bbamcr.2017.01.001 Google Scholar
  95. Rieusset J, Fauconnier J, Paillard M, Belaidi E, Tubbs E, Chauvin MA, Durand A, Bravard A, Teixeira G, Bartosch B, Michelet M, Theurey P, Vial G, Demion M, Blond E, Zoulim F, Gomez L, Vidal H, Lacampagne A, Ovize M (2016) Disruption of calcium transfer from ER to mitochondria links alterations of mitochondria-associated ER membrane integrity to hepatic insulin resistance. Diabetologia 59(3):614–623PubMedCrossRefGoogle Scholar
  96. Röhrig F, Schulze A (2016) The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer 16(11):732–749PubMedCrossRefGoogle Scholar
  97. Rychkov GY, Barritt GJ (2011) Expression and function of TRP channels in liver cells. Adv Exp Med Biol 704:667–686PubMedCrossRefGoogle Scholar
  98. Rychkov G, Brereton HM, Harland ML, Barritt GJ (2001) Plasma membrane Ca2+ release-activated Ca2+ channels with a high selectivity for Ca2+ identified by patch-clamp recording in rat liver cells. Hepatology 33(4):938–947PubMedCrossRefGoogle Scholar
  99. Samuel VT, Shulman GI (2012) Mechanisms for insulin resistance: common threads and missing links. Cell 148(5):852–871PubMedPubMedCentralCrossRefGoogle Scholar
  100. Samuel VT, Shulman GI (2016) The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Invest 126(1):12–22PubMedPubMedCentralCrossRefGoogle Scholar
  101. Sawanobori T, Takanashi H, Hiraoka M, Iida Y, Kamisaka K, Maezawa H (1989) Electrophysiological properties of isolated rat liver cells. J Cell Physiol 139(3):580–585PubMedCrossRefGoogle Scholar
  102. Scherer A, Dufour JF (2016) Treatment of non-alcoholic fatty liver disease. Dig Dis 34(Suppl 1):27–31PubMedCrossRefGoogle Scholar
  103. Scrimgeour N, Litjens T, Ma L, Barritt GJ, Rychkov GY (2009) Properties of Orai1 mediated store-operated current depend on the expression levels of STIM1 and Orai1 proteins. J Physiol (Lond) 587(Pt 12):2903–2918CrossRefGoogle Scholar
  104. Scrimgeour NR, Wilson DP, Barritt GJ, Rychkov GY (2014) Structural and stoichiometric determinants of Ca2+ release-activated Ca2+ (CRAC) channel Ca2+-dependent inactivation. Biochim Biophys Acta 1838(5):1281–1287PubMedCrossRefGoogle Scholar
  105. Sharma A, Umar S, Kar P, Singh K, Sachdev M, Goel A (2016) A new type of biocompatible fluorescent probe AFN for fixed and live cell imaging of intracellular lipid droplets. Analyst 141(1):137–143PubMedCrossRefGoogle Scholar
  106. Srikanth S, Ribalet B, Gwack Y (2013) Regulation of CRAC channels by protein interactions and post-translational modification. Channels (Austin) 7(5):354–363CrossRefGoogle Scholar
  107. Srivats S, Balasuriya D, Pasche M, Vistal G, Edwardson JM, Taylor CW, Murrell-Lagnado RD (2016) Sigma1 receptors inhibit store-operated Ca2+ entry by attenuating coupling of STIM1 to Orai1. J Cell Biol 213(1):65–79PubMedPubMedCentralCrossRefGoogle Scholar
  108. Steenks M, van Baal MC, Nieuwenhuijs VB, de Bruijn MT, Schiesser M, Teo MH, Callahan T, Padbury RT, Barritt GJ (2010) Intermittent ischaemia maintains function after ischaemia reperfusion in steatotic livers. HPB (Oxford) 12(4):250–261PubMedCentralCrossRefGoogle Scholar
  109. Striggow F, Bohnensack R (1993) Verapamil and diltiazem inhibit receptor-operated calcium channels and intracellular calcium oscillations in rat hepatocytes. FEBS Lett 318(3):341–344PubMedCrossRefGoogle Scholar
  110. Sun Z, Lazar MA (2013) Dissociating fatty liver and diabetes. Trends Endocrinol Metab 24(1):4–12PubMedCrossRefGoogle Scholar
  111. Thomas A, Delaville F (1991) The use of fluorescent indicators for measurements of cytosolic-free calcium concentration in cell populations and single cells. In: McCormack JG, Cobbold PH (eds) Cellular calcium: a practical approach. IRL, Oxford, pp 1–54Google Scholar
  112. Tilg H, Moschen AR, Roden M (2017) NAFLD and diabetes mellitus. Nat Rev Gastroenterol Hepatol 14(1):32–42PubMedCrossRefGoogle Scholar
  113. To MS, Aromataris EC, Castro J, Roberts ML, Barritt GJ, Rychkov GY (2010) Mitochondrial uncoupler FCCP activates proton conductance but does not block store-operated Ca(2+) current in liver cells. Arch Biochem Biophys 495(2):152–158PubMedCrossRefGoogle Scholar
  114. Vaca L (2010) SOCIC: the store-operated calcium influx complex. Cell Calcium 47(3):199–209PubMedCrossRefGoogle Scholar
  115. Walther TC, Farese RV Jr (2012) Lipid droplets and cellular lipid metabolism. Annu Rev Biochem 81:687–714PubMedPubMedCentralCrossRefGoogle Scholar
  116. Wang S, Kaufman RJ (2014) How does protein misfolding in the endoplasmic reticulum affect lipid metabolism in the liver? Curr Opin Lipidol 25(2):125–132PubMedCrossRefGoogle Scholar
  117. Wei Y, Wang D, Gentile CL, Pagliassotti MJ (2009) Reduced endoplasmic reticulum luminal calcium links saturated fatty acid-mediated endoplasmic reticulum stress and cell death in liver cells. Mol Cell Biochem 331(1–2):31–40PubMedPubMedCentralCrossRefGoogle Scholar
  118. Wilson CH, Ali ES, Scrimgeour N, Martin AM, Hua J, Tallis GA, Rychkov GY, Barritt GJ (2015) Steatosis inhibits liver cell store-operated Ca(2)(+) entry and reduces ER Ca(2)(+) through a protein kinase C-dependent mechanism. Biochem J 466(2):379–390PubMedCrossRefGoogle Scholar
  119. Wong CR, Nguyen MH, Lim JK (2016) Hepatocellular carcinoma in patients with non-alcoholic fatty liver disease. World J Gastroenterol 22(37):8294–8303PubMedPubMedCentralCrossRefGoogle Scholar
  120. Woods NM, Cuthbertson KS, Cobbold PH (1986) Repetitive transient rises in cytoplasmic free calcium in hormone-stimulated hepatocytes. Nature 319(6054):600–602PubMedCrossRefGoogle Scholar
  121. Woods NM, Cuthbertson KS, Cobbold PH (1987) Agonist-induced oscillations in cytoplasmic free calcium concentration in single rat hepatocytes. Cell Calcium 8(1):79–100PubMedCrossRefGoogle Scholar
  122. Wu J, Danielsson A, Lindstrom P, Karlsson K, Sehlin J (1995) Protective effects of calcium channel blockers on acute bromobenzene toxicity to isolated rat hepatocytes. Inhibition of phenylephrine-induced calcium oscillations. Scand J Gastroenterol 30(6):590–600PubMedCrossRefGoogle Scholar
  123. Xiao C, Giacca A, Lewis GF (2011) Sodium phenylbutyrate, a drug with known capacity to reduce endoplasmic reticulum stress, partially alleviates lipid-induced insulin resistance and beta-cell dysfunction in humans. Diabetes 60(3):918–924PubMedPubMedCentralCrossRefGoogle Scholar
  124. Young B, Heath JW (2000) Liver and pancreas Wheater’s functional histology, 4th edn. Churchill Livingstone, Edinburgh, pp 274–275Google Scholar
  125. Zhang C, Thomas DW (2016) Stromal Interaction Molecule 1 rescues store-operated calcium entry and protects NG115-401L cells against cell death induced by endoplasmic reticulum and mitochondrial oxidative stress. Neurochem Int 97:137–145PubMedCrossRefGoogle Scholar
  126. Zhang J, Li Y, Jiang S, Yu H, An W (2014) Enhanced endoplasmic reticulum SERCA activity by overexpression of hepatic stimulator substance gene prevents hepatic cells from ER stress-induced apoptosis. Am J Physiol Cell Physiol 306(3):C279–C290PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Eunüs S. Ali
    • 1
    • 2
  • Grigori Y. Rychkov
    • 3
    • 4
  • Greg J. Barritt
    • 1
    • 2
    Email author
  1. 1.Department of Medical Biochemistry, School of MedicineFlinders UniversityAdelaideAustralia
  2. 2.Centre for Neuroscience, School of MedicineFlinders UniversityAdelaideAustralia
  3. 3.School of MedicineThe University of AdelaideAdelaideAustralia
  4. 4.South Australian Health and Medical Research InstituteAdelaideAustralia

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