DOI QR코드

DOI QR Code

Increased Hepatic Lipogenesis Elevates Liver Cholesterol Content

  • Berger, Jean-Mathieu (Departments of Internal Medicine and Molecular Genetics, University of Texas Southwestern Medical Center) ;
  • Moon, Young-Ah (Department of Molecular Medicine, Inha University College of Medicine)
  • 투고 : 2020.07.07
  • 심사 : 2021.02.07
  • 발행 : 2021.02.28

초록

Cardiovascular diseases (CVDs) are the most common cause of death in patients with nonalcoholic fatty liver disease (NAFLD) and dyslipidemia is considered at least partially responsible for the increased CVD risk in NAFLD patients. The aim of the present study is to understand how hepatic de novo lipogenesis influences hepatic cholesterol content as well as its effects on the plasma lipid levels. Hepatic lipogenesis was induced in mice by feeding a fat-free/high-sucrose (FF/HS) diet and the metabolic pathways associated with cholesterol were then analyzed. Both liver triglyceride and cholesterol contents were significantly increased in mice fed an FF/HS diet. Activation of fatty acid synthesis driven by the activation of sterol regulatory element binding protein (SREBP)-1c resulted in the increased liver triglycerides. The augmented cholesterol content in the liver could not be explained by an increased cholesterol synthesis, which was decreased by the FF/HS diet. HMG-CoA reductase protein level was decreased in mice fed an FF/HS diet. We found that the liver retained more cholesterol through a reduced excretion of bile acids, a reduced fecal cholesterol excretion, and an increased cholesterol uptake from plasma lipoproteins. Very low-density lipoproteintriglyceride and -cholesterol secretion were increased in mice fed an FF/HS diet, which led to hypertriglyceridemia and hypercholesterolemia in Ldlr-/- mice, a model that exhibits a more human like lipoprotein profile. These findings suggest that dietary cholesterol intake and cholesterol synthesis rates cannot only explain the hypercholesterolemia associated with NAFLD, and that the control of fatty acid synthesis should be considered for the management of dyslipidemia.

키워드

과제정보

This work was supported by grants from the National Research Foundation of Korea funded by the Korean government (2018R1A2B6007576), the National Institutes of Health (HL-20948), and the Leducq Foundation (5200829301). The authors thank Sijeong Bae (Department of Molecular Medicine, Inha University College of Medicine) Angel Loza Valdes, Ajit Kumar Koduri, Tuyet Dang, Judith Sanchez, Norma Anderson, and Lisa Beatty (Department of Molecular Genetics, UT Southwestern Medical Center), and Abhijit Bugde (the Live Cell Imaging Core Facility, UT Southwestern Medical Center) for their technical assistance. The authors also thank Dr. Youngah Jo for providing the anti-HMG CoA-R antibody and Dr. Jay Horton for scientific advice.

참고문헌

  1. Acton, S., Rigotti, A., Landschulz, K.T., Xu, S., Hobbs, H.H., and Krieger, M. (1996). Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 271, 518-520. https://doi.org/10.1126/science.271.5248.518
  2. Angulo, P. (2002). Nonalcoholic fatty liver disease. N. Engl. J. Med. 346, 1221-1231. https://doi.org/10.1056/NEJMra011775
  3. Anstee, Q.M., Targher, G., and Day, C.P. (2013). Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat. Rev. Gastroenterol. Hepatol. 10, 330-344. https://doi.org/10.1038/nrgastro.2013.41
  4. Browning, J.D., Szczepaniak, L.S., Dobbins, R., Nuremberg, P., Horton, J.D., Cohen, J.C., Grundy, S.M., and Hobbs, H.H. (2004). Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40, 1387-1395. https://doi.org/10.1002/hep.20466
  5. Brundert, M., Heeren, J., Merkel, M., Carambia, A., Herkel, J., Groitl, P., Dobner, T., Ramakrishnan, R., Moore, K.J., and Rinninger, F. (2011). Scavenger receptor CD36 mediates uptake of high density lipoproteins in mice and by cultured cells. J. Lipid Res. 52, 745-758. https://doi.org/10.1194/jlr.M011981
  6. Chatrath, H., Vuppalanchi, R., and Chalasani, N. (2012). Dyslipidemia in patients with nonalcoholic fatty liver disease. Semin. Liver Dis. 32, 22-29. https://doi.org/10.1055/s-0032-1306423
  7. Chong, M.F.F., Fielding, B.A., and Frayn, K.N. (2007). Metabolic interaction of dietary sugars and plasma lipids with a focus on mechanisms and de novo lipogenesis. Proc. Nutr. Soc. 66, 52-59. https://doi.org/10.1017/S0029665107005290
  8. Cohen, D.E. and Fisher, E.A. (2013). Lipoprotein metabolism, dyslipidemia, and nonalcoholic fatty liver disease. Semin. Liver Dis. 33, 380-388. https://doi.org/10.1055/s-0033-1358519
  9. Cohen, J.C., Horton, J.D., and Hobbs, H.H. (2011). Human fatty liver disease: old questions and new insights. Science 332, 1519-1523. https://doi.org/10.1126/science.1204265
  10. Connelly, M.A. and Williams, D.L. (2004). Scavenger receptor BI: a scavenger receptor with a mission to transport high density lipoprotein lipids. Curr. Opin. Lipidol. 15, 287-295. https://doi.org/10.1097/00041433-200406000-00008
  11. DeBose-Boyd, R.A. (2008). Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase. Cell Res. 18, 609-621. https://doi.org/10.1038/cr.2008.61
  12. Donnelly, K.L., Smith, C.I., Schwarzenberg, S.J., Jessurun, J., Boldt, M.D., and Parks, E.J. (2005). Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Invest. 115, 1343-1351. https://doi.org/10.1172/JCI23621
  13. Endemann, G., Stanton, L.W., Madden, K.S., Bryant, C.M., White, R.T., and Protter, A.A. (1993). CD36 is a receptor for oxidized low density lipoprotein. J. Biol. Chem. 268, 11811-11816. https://doi.org/10.1016/S0021-9258(19)50272-1
  14. Engelking, L.J., Kuriyama, H., Hammer, R.E., Horton, J.D., Brown, M.S., Goldstein, J.L., and Liang, G. (2004). Overexpression of Insig-1 in the livers of transgenic mice inhibits SREBP processing and reduces insulinstimulated lipogenesis. J. Clin. Invest. 113, 1168-1175. https://doi.org/10.1172/JCI20978
  15. Febbraio, M. and Silverstein, R.L. (2007). CD36: implications in cardiovascular disease. Int. J. Biochem. Cell Biol. 39, 2012-2030. https://doi.org/10.1016/j.biocel.2007.03.012
  16. Gerloff, T., Stieger, B., Hagenbuch, B., Madon, J., Landmann, L., Roth, J., Hofmann, A.F., and Meier, P.J. (1998). The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J. Biol. Chem. 273, 10046-10050. https://doi.org/10.1074/jbc.273.16.10046
  17. Goldstein, J.L., Basu, S.K., and Brown, M.S. (1983). Receptor-mediated endocytosis of low-density lipoprotein in cultured cells. Methods Enzymol. 98, 241-260. https://doi.org/10.1016/0076-6879(83)98152-1
  18. Hellerstein, M.K. and Parks, E.J. (2000). Carbohydrate-induced hypertriacylglycerolemia: historical perspective and review of biological mechanisms. Am. J. Clin. Nutr. 71, 412-433. https://doi.org/10.1093/ajcn/71.2.412
  19. Horton, J.D., Cohen, J.C., and Hobbs, H.H. (2009). PCSK9: a convertase that coordinates LDL catabolism. J. Lipid Res. 50 Suppl, S172-S177. https://doi.org/10.1194/jlr.R800091-JLR200
  20. Horton, J.D., Goldstein, J.L., and Brown, M.S. (2002). SREBPs:activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125-1131. https://doi.org/10.1172/JCI15593
  21. Horton, J.D., Shah, N.A., Warrington, J.A., Anderson, N.N., Park, S.W., Brown, M.S., and Goldstein, J.L. (2003). Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc. Natl. Acad. Sci. U. S. A. 100, 12027-12032. https://doi.org/10.1073/pnas.1534923100
  22. Horton, J.D., Shimano, H., Hamilton, R.L., Brown, M.S., and Goldstein, J.L. (1999). Disruption of LDL receptor gene in transgenic SREBP-1a mice unmasks hyperlipidemia resulting from production of lipid-rich VLDL. J. Clin. Invest. 103, 1067-1076. https://doi.org/10.1172/JCI6246
  23. Horton, J.D. and Shimomura, I. (1999). SREBPs: activators of cholesterol and fatty acid biosynthesis. Curr. Opin. Lipidol. 10, 143-150. https://doi.org/10.1097/00041433-199904000-00008
  24. Howard, B.V. (1987). Lipoprotein metabolism in diabetes mellitus. J. Lipid Res. 28, 613-628. https://doi.org/10.1016/S0022-2275(20)38659-4
  25. Hudgins, L.C., Hellerstein, M., Seidman, C., Neese, R., Diakun, J., and Hirsch, J. (1996). Human fatty acid synthesis is stimulated by a eucaloric low fat, high carbohydrate diet. J. Clin. Invest. 97, 2081-2091. https://doi.org/10.1172/jci118645
  26. Ikonen, E. (2008). Cellular cholesterol trafficking and compartmentalization. Nat. Rev. Mol. Cell Biol. 9, 125-138. https://doi.org/10.1038/nrm2336
  27. Iritani, N., Nishimoto, N., Katsurada, A., and Fukuda, H. (1992). Regulation of hepatic lipogenic enzyme gene expression by diet quantity in rats fed a fat-free, high carbohydrate diet. J. Nutr. 122, 28-36. https://doi.org/10.1093/jn/122.1.28
  28. Johnson, B.M. and DeBose-Boyd, R.A. (2018). Underlying mechanisms for sterol-induced ubiquitination and ER-associated degradation of HMGCoA reductase. Semin. Cell Dev. Biol. 81, 121-128. https://doi.org/10.1016/j.semcdb.2017.10.019
  29. Kim, C.W., Addy, C., Kusunoki, J., Anderson, N.N., Deja, S., Fu, X., Burgess, S.C., Li, C., Ruddy, M., Chakravarthy, M., et al. (2017). Acetyl-CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation. Cell Metab. 26, 394-406.e396. https://doi.org/10.1016/j.cmet.2017.07.009
  30. Kim, M.J., Choi, W.G., Ahn, K.J., Chae, I.G., Yu, R., and Back, S.H. (2020). Reduced EGFR level in eIF2 phosphorylation-deficient hepatocytes is responsible for susceptibility to oxidative stress. Mol. Cells 43, 264-275. https://doi.org/10.14348/molcells.2020.2197
  31. Kim, T.S. and Freake, H.C. (1996). High carbohydrate diet and starvation regulate lipogenic mRNA in rats in a tissue-specific manner. J. Nutr. 126, 611-617. https://doi.org/10.1093/jn/126.3.611
  32. Lambert, J.E., Ramos-Roman, M.A., Browning, J.D., and Parks, E.J. (2014). Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology 146, 726-735. https://doi.org/10.1053/j.gastro.2013.11.049
  33. Makadia, S.S., Blaha, M., Keenan, T., Ndumele, C., Jones, S., DeFilippis, A., Martin, S., Kohli, P., Conceicao, R., Carvalho, J., et al. (2013). Relation of hepatic steatosis to atherogenic dyslipidemia. Am. J. Cardiol. 112, 1599-1604. https://doi.org/10.1016/j.amjcard.2013.08.001
  34. Matsuda, M., Korn, B.S., Hammer, R.E., Moon, Y.A., Komuro, R., Horton, J.D., Goldstein, J.L., Brown, M.S., and Shimomura, I. (2001). SREBP cleavageactivating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation. Genes Dev. 15, 1206-1216. https://doi.org/10.1101/gad.891301
  35. May, C.L., Berger, J.M., Lespine, A., Pillot, B., Prieur, X., Letessier, E., Hussain, M.M., Collet, X., Cariou, B., and Costet, P. (2013). Transintestinal cholesterol excretion is an active metabolic process modulated by PCSK9 and statin involving ABCB1. Arterioscler. Thromb. Vasc. Biol. 33, 1484-1493. https://doi.org/10.1161/ATVBAHA.112.300263
  36. Moon, Y.A., Hammer, R.E., and Horton, J.D. (2009). Deletion of ELOVL5 leads to fatty liver through activation of SREBP-1c in mice. J. Lipid Res. 50, 412-423. https://doi.org/10.1194/jlr.M800383-JLR200
  37. Moon, Y.A., Liang, G., Xie, X., Frank-Kamenetsky, M., Fitzgerald, K., Koteliansky, V., Brown, M.S., Goldstein, J.L., and Horton, J.D. (2012). The Scap/SREBP pathway is essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animals. Cell Metab. 15, 240-246. https://doi.org/10.1016/j.cmet.2011.12.017
  38. Moon, Y.A., Ochoa, C.R., Mitsche, M.A., Hammer, R.E., and Horton, J.D. (2014). Deletion of ELOVL6 blocks the synthesis of oleic acid but does not prevent the development of fatty liver or insulin resistance. J. Lipid Res. 55, 2597-2605. https://doi.org/10.1194/jlr.M054353
  39. Okazaki, H., Goldstein, J.L., Brown, M.S., and Liang, G. (2010). LXR-SREBP1c-phospholipid transfer protein axis controls very low density lipoprotein (VLDL) particle size. J. Biol. Chem. 285, 6801-6810. https://doi.org/10.1074/jbc.M109.079459
  40. Rong, S., Cortes, V.A., Rashid, S., Anderson, N.N., McDonald, J.G., Liang, G., Moon, Y.A., Hammer, R.E., and Horton, J.D. (2017). Expression of SREBP-1c requires SREBP-2-mediated generation of a sterol ligand for LXR in livers of mice. eLife 6, e25015. https://doi.org/10.7554/elife.25015
  41. Sanders, F.W.B., Acharjee, A., Walker, C., Marney, L., Roberts, L.D., Imamura, F., Jenkins, B., Case, J., Ray, S., Virtue, S., et al. (2018). Hepatic steatosis risk is partly driven by increased de novo lipogenesis following carbohydrate consumption. Genome Biol. 19, 79. https://doi.org/10.1186/s13059-018-1439-8
  42. Semenkovich, C.F. (2006). Insulin resistance and atherosclerosis. J. Clin. Invest. 116, 1813-1822. https://doi.org/10.1172/JCI29024
  43. Shimano, H., Horton, J.D., Hammer, R.E., Shimomura, I., Brown, M.S., and Goldstein, J.L. (1996). Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP1a. J. Clin. Invest. 98, 1575-1584. https://doi.org/10.1172/JCI118951
  44. Shimomura, I., Shimano, H., Korn, B.S., Bashmakov, Y., and Horton, J.D. (1998). Nuclear sterol regulatory element-binding proteins activate genes responsible for the entire program of unsaturated fatty acid biosynthesis in transgenic mouse liver. J. Biol. Chem. 273, 35299-35306. https://doi.org/10.1074/jbc.273.52.35299
  45. Sukonina, V., Lookene, A., Olivecrona, T., and Olivecrona, G. (2006). Angiopoietin-like protein 4 converts lipoprotein lipase to inactive monomers and modulates lipase activity in adipose tissue. Proc. Natl. Acad. Sci. U. S. A. 103, 17450-17455. https://doi.org/10.1073/pnas.0604026103
  46. Targher, G., Day, C.P., and Bonora, E. (2010). Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N. Engl. J. Med. 363, 1341-1350. https://doi.org/10.1056/NEJMra0912063
  47. Turley, S.D., Daggy, B.P., and Dietschy, J.M. (1996). Effect of feeding psyllium and cholestyramine in combination on low density lipoprotein metabolism and fecal bile acid excretion in hamsters with dietary-induced hypercholesterolemia. J. Cardiovasc. Pharmacol. 27, 71-79. https://doi.org/10.1097/00005344-199601000-00012
  48. Weigand, W., Hannappel, E., and Brand, K. (1980). Effect of starvation and refeeding a high-protein or high-carbohydrate diet on lipid composition and glycogen content of rat livers in relation to age. J. Nutr. 110, 669-674. https://doi.org/10.1093/jn/110.4.669
  49. Xie, C., Woollett, L.A., Turley, S.D., and Dietschy, J.M. (2002). Fatty acids differentially regulate hepatic cholesteryl ester formation and incorporation into lipoproteins in the liver of the mouse. J. Lipid Res. 43, 1508-1519. https://doi.org/10.1194/jlr.M200146-JLR200
  50. Yao, Z. and Wang, Y. (2012). Apolipoprotein C-III and hepatic triglyceriderich lipoprotein production. Curr. Opin. Lipidol. 23, 206-212. https://doi.org/10.1097/MOL.0b013e328352dc70
  51. Yazdanyar, A. and Jiang, X.C. (2012). Liver phospholipid transfer protein (PLTP) expression with a PLTP-null background promotes very low-density lipoprotein production in mice. Hepatology 56, 576-584. https://doi.org/10.1002/hep.25648
  52. Ye, J., Li, J.Z., Liu, Y., Li, X., Yang, T., Ma, X., Li, Q., Yao, Z., and Li, P. (2009). Cideb, an ER- and lipid droplet-associated protein, mediates VLDL lipidation and maturation by interacting with apolipoprotein B. Cell Metab. 9, 177-190. https://doi.org/10.1016/j.cmet.2008.12.013
  53. Yu, L., Hammer, R.E., Li-Hawkins, J., von Bergmann, K., Lutjohann, D., Cohen, J.C., and Hobbs, H.H. (2002). Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc. Natl. Acad. Sci. U. S. A. 99, 16237-16242. https://doi.org/10.1073/pnas.252582399
  54. Zhang, J., Zamani, M., Thiele, C., Taher, J., Alipour, M.A., Yao, Z., and Adeli, K. (2017). AUP1 (ancient ubiquitous protein 1) is a key determinant of hepatic very-low density lipoprotein assembly and secretion. Arterioscler. Thromb. Vasc. Biol. 37, 633-642. https://doi.org/10.1161/ATVBAHA.117.309000
  55. Zhang, R. (2012). Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels. Biochem. Biophys. Res. Commun. 424, 786-792. https://doi.org/10.1016/j.bbrc.2012.07.038

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