肝細胞癌是全球第四大致死的癌症，肝癌的危險因素包括B型和C型肝炎病毒感染、飲酒過量、黃麴黴毒素、和非酒精性脂肪性肝病（NAFLD），台灣自1984年實施全面B型肝炎疫苗接種以及抗C型肝炎病毒新藥物，病毒性肝炎引發的肝癌將逐漸減少，取而代之的是非酒精性脂肪性肝病引發的肝癌。CD36（也稱為脂肪酸轉移酶（FAT））在肝臟中主要發揮著脂肪酸攝取及結合氧化的低密度脂蛋白等作用，在非病毒性肝炎引發的肝癌患者中發現其基因擴增及表達上升。CD36高表達引起肝癌的作用以及CD36與飲食因子之間的協同作用仍不清楚。使用的CD36轉基因斑馬魚處理不同飲食，我的目的是了解CD36表達上升會對肝臟造成什麼影響、CD36與飲食因子之間的協同作用，並利用此平台篩選抗脂肪累積和抗肝癌的藥物。
首先，我發現與野生種對照相比，CD36過度表達增加了脂質積累。我觀察到用高脂飼料餵養15天的CD36轉基因幼魚增加了脂質積累。0.25％乙醇處理或4％果糖處理對CD36轉基因魚的脂質積累沒有顯著影響，表明CD36轉基因魚對高脂肪飲食特異性敏感。此外，我觀察到用高脂飼料餵養15天的CD36轉基因幼魚會有脂肪生成，發炎反應和內質網壓力相關基因的表達增加。我還發現CD36轉基因幼魚與野生種相比有更高的三酸甘油酯的含量。接著，我利用高脂飼料餵養30天的CD36轉基因幼魚中觀察到肝細胞癌的形成。另外，用正常飲食餵養的CD36轉基因魚在3月大時有肝細胞癌的形成。我發現使用來自植物（香椿）的萃取物（TB）藉由個體油紅染色結果發現可以有效地減少CD36胚胎的脂質積累。最後，透過異種移植試驗結果我發現TB具有抑制肝癌細胞株Hep3B和Huh7的細胞增殖。總結，我證明了CD36在脂質體內平衡和肝細胞瘤細胞增殖之間的相互關係，並證明了香椿樹皮提取物可能是非酒精性肝炎和肝細胞癌的有用治療藥劑。

Hepatocellular carcinoma (HCC) ranks as the fourth leading cause of cancer-related death worldwide. Hepatitis B and C virus infection, excessive alcohol consumption, aflatoxin contamination and non-alcoholic fatty liver disease (NAFLD) are the main risk factors for HCC. Due to global vaccination and antiviral medications, virus related HCC will potentially be eradicated, and NAFLD will soon become the commonest cause of HCC. CD36 (also known as fatty acid translocase (FAT)) plays a role in fatty acid uptake and oxidized low-density lipoprotein in the liver, its gene amplification and overexpression was found in non-viral induced liver cancer patients. The role of CD36 overexpression in causing HCC, and the synergism between CD36 and dietary factors remains unclear. Using transgenic zebrafish treated with different diet, I aimed to understand the function of CD36 overexpression on lipid accumulation and liver cancer formation, synergism between CD36 and dietary factors, and use this platform to screen for anti-lipid accumulation and anti-hepatocarcinoma drugs.
Firstly, I found CD36 overexpression increase the lipid accumulation compare to AB wild-type control. High fat diet increased lipid accumulation in CD36 transgenic fish, but 0.25% ethanol treatment or 4% fructose treatment has no significant effect on lipid accumulation in CD36 transgenic fish, indicating the CD36 transgenic fish is specific sensitive to high fat diet. In addition, I observed increase expression of lipogenesis, inflammation and ER stress in CD36 transgenic larvae fed with high fat diet for 10 days starting 5 day post fertilization. I also found CD36 transgenic larva exhibit higher triacylglycerol level compare to wild-type fish. Moreover, I discovery HCC formation in CD36 transgenic larvae fed with high fat diet at one month of age. Furthermore, CD36 transgenic fish fed with normal diet developed into HCC at three month of age. Using the different extract from plant (Toona sinensis), I found extract (TB) can effectively reduce lipid accumulation of CD36 embryos as revealed by whole-mount oil red staining. Finally, I discovered TB could inhibit the cellular proliferation of Hep3B and Huh7 hepatoma cell lines by xenotransplantation assay. Together, I demonstrated the interrelationship among CD36 in lipid homeostasis and hepatoma cell proliferation and demonstrated the bark extract from Toona sinensis might be useful therapeutic agents for NAFLD and HCC.
 

Abstract I
中文摘要 II
致謝 III
Content V
Chapter 1. Introduction 1
1.1 Dietary fat intake and disease 1
1.2 Non-alcoholic fatty liver disease (NAFLD) 1
1.3 Hepatocellular carcinoma 2
1.4 Cluster of differentiation 36 (CD36) 3
1.5 CD36 in NAFLD and HCC 5
1.6 Zebrafish as human disease models 5
Chapter 2. Materials and Methods 7
2.1 Gateway cloning 7
2.2 Microinjection 8
2.3 Zebrafish maintain and care 8
2.4 Zebrafish larvae feeding and treatment 8
2.4.1 Fructose treatment 9
2.4.2 Ethanol treatment 9
2.4.3 High Fat Diet treatment 9
2.5 Whole mount Oil Red O stain 10
2.6 RNA extraction 10
2.7 Reverse transcription polymerase chain reaction 11
2.9 Tissue collection 12
2.10 Immunohistochemistry stain (IHC) 12
2.11 Triacylglycerol assay 13
2.12 Cell culture 13
2.13 Cell viability 13
2.14 Xenotransplantation 14
Chapter 3. Results 16
3.1 CD36 overexpression increase the lipid accumulation compare to AB wild-type control, high-fat-diet further increased the lipid accumulation 16
3.2 Ethanol and Fructose treatment did not induce lipid accumulation in CD36 transgenic fish 16
3.3 Gene change in the CD36 overexpression transgenic zebrafish larvae 17
3.3 CD36 overexpression led to higher level of triacylglycerol in zebrafish larvae 18
3.4 CD36 transgenic fish developed HCC at 30 days feed with HFD starting 5 dpf 18
3.5 CD36 transgenic developed into HCC at 3 month of age with normal diet 20
3.7 Plant (Toona sinensis) extract (TB) effectively reduced lipid accumulation in CD36 transgenic larvae 21
3.8 Toona sinensis extract could reduce hepatoma cell survival and cell proliferation 22
Chapter 4. Discussion 23
4.1 CD36 overexpression in liver are associated with high fat uptake induced steatosis in models 23
4.2 Why does liver damage in 5M CD36 overexpression transgenic not as severe as 3M? 24
4.3 Whether lipid accumulation and HCC development on CD36 transgenic zebrafish will be more severe with abcg1 or abcg4a deletion? 25
4.4 CD36 overexpression transgenic fish can be a useful drug screening model for anti-lipid accumulation or anti-liver cancer drugs. 25
4.5 The effect of lipid accumulation and HCC formation in CD36 overexpression zebrafish treated with ERK inhibitor. 26
4.6 The effect of lipid accumulation and HCC formation in CD36 adult zebrafish fed with TB by oral feeding 26
Figures 28
Figure 1. Establishment of CD36 over-expression transgenic fish 29
Figure 2. CD36 overexpression induce lipid accumulation in larvae high fat diet for 10 days further increased the lipid accumulation 33
Figure 3. Ethanol and fructose did not increase lipid accumulation in CD36 transgenic fish 35
Figure 4. Expression of lipid and cholesterol synthesis, lipid oxidation, ER stress and inflammation of CD36 larvae fed with high fat diet for 10 days 41
Figure 5. CD36 overexpression induce lipid accumulation in larvae with 25 days of high fat treatment 45
Figure 6. Expression of lipid and cholesterol synthesis, lipid oxidation, ER stress and inflammation of CD36 larvae fed with high fat diet for 25 days 51
Figure 7. CD36 transgenic fish fed with high-fat diet since 5 dpf developed HCC at 1 month of age 53
Figure 8. CD 36 transgenic fish under normal diet induced liver damage and cancer formation at 3 month of age 56
Figure 9. CD36 overexpression up-regulate cell proliferation related marker in 3 months old zebrafish 59
Figure 10. H&E stain analysis of 5 months old of CD36 overexpression zebrafish 62
Figure 11. CD36 overexpression up-regulate cell proliferation related marker in 5 months old zebrafish 65
Figure 12. Toona sinensis extract can reduce lipid accumulation in CD36 overexpression larvae 67
Figure 13. The survival rate of hepatoma cell (Huh7, HepG2 and Hep3B) were inhibited by Toona sinensis extract 69
Figure 14. Anti-proliferation ability of Toona sinensis extract were identified by xenotransplantation assay 71
Tables 72
Table 1. The primer list for qPCR in CD36 larvae with diet treatment 72
Table 2. The cell proliferation primer list for qPCR in CD36 transgenic zebrafish 73
Supplementary data. 75
References 99

AbumradSB, N.A., El-MaghrabiS, M.R., Amrill, E.-Z., LopezS, E., and Grimaldil, P.A. (1993). Cloning of a Rat Adipocyte Membrane Protein Implicated in Binding or Transport of Long-chain Fatty Acids That Is Induced during Preadipocyte Differentiation.
Ahmadian, M., Duncan, R.E., Jaworski, K., Sarkadi-Nagy, E., and Sul, H.S. (2007). Triacylglycerol metabolism in adipose tissue. Future Lipidol 2, 229-237.
Balogh, J., Victor, D., 3rd, Asham, E.H., Burroughs, S.G., Boktour, M., Saharia, A., Li, X., Ghobrial, R.M., and Monsour, H.P., Jr. (2016). Hepatocellular carcinoma: a review. J Hepatocell Carcinoma 3, 41-53.
Bellentani, S., Scaglioni, F., Marino, M., and Bedogni, G. (2010). Epidemiology of non-alcoholic fatty liver disease. Dig Dis 28, 155-161.
Brown, A.J. (2008). Viral hepatitis and fatty liver disease: how an unwelcome guest makes pate of the host. Biochem J 416, e15-17.
Caldwell, S.H., Crespo, D.M., Kang, H.S., and Al-Osaimi, A.M.S. (2004). Obesity and hepatocellular carcinoma. Gastroenterology 127, S97-S103.
Calvo, D., Gómez-Coronado, D., Suárez, Y., Lasunción, M.A., and Vega, M.A. (2019). Human CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, and VLDL.
Campbell, S.E., Tandon, N.N., Woldegiorgis, G., Luiken, J.J., Glatz, J.F., and Bonen, A. (2004). A novel function for fatty acid translocase (FAT)/CD36: involvement in long chain fatty acid transfer into the mitochondria. J Biol Chem 279, 36235-36241.
Chabowski, A., Coort, S.L.M., Calles-Escandon, J., Tandon, N.N., Glatz, J.F.C., Luiken, J.J.F.P., and Bonen1, A. (2004). Insulin stimulates fatty acid transport by regulating expression of FAT/CD36 but not FABPpm.
Chen, Y.-C., Chien, L.-H., Huang, B.-M., and Chia, Y.-C. (2014). Toona sinensis (aqueous leaf extracts) induces apoptosis through the generation of ROS and activation of intrinsic apoptotic pathways in human renal carcinoma cells. Journal of Functional Foods 7, 362-372.
Chou, Y.T., Chen, L.Y., Tsai, S.L., Tu, H.C., Lu, J.W., Ciou, S.C., Wang, H.D., and Yuh, C.H. (2019). Ribose-5-phosphate isomerase A overexpression promotes liver cancer development in transgenic zebrafish via activation of ERK and beta-catenin pathways. Carcinogenesis 40, 461-473.
Coburn, C.T., Knapp, F.F., Jr., Febbraio, M., Beets, A.L., Silverstein, R.L., and Abumrad, N.A. (2000). Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J Biol Chem 275, 32523-32529.
Dai, W., Wang, K., Zheng, X., Chen, X., Zhang, W., Zhang, Y., Hou, J., and Liu, L. (2015). High fat plus high cholesterol diet lead to hepatic steatosis in zebrafish larvae: a novel model for screening anti-hepatic steatosis drugs. Nutr Metab (Lond) 12, 42.
DAM, R.M.V., WILLETT, W.C., RIMM, E.B., STAMPFER, M.J., and HU, F.B. (2002). Dietary Fat and Meat Intake in Relation to Risk of Type 2 Diabetes in Men. Diabetes Care 25:417–424.
DIRAISON, F., and BEYLOT, M. (1998). Role of human liver lipogenesis and reesterification in triglycerides secretion and in FFA reesterification. The American journal of physiology.
El-Serag, H.B., and Rudolph, K.L. (2007). Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132, 2557-2576.
Enciu, A.M., Radu, E., Popescu, I.D., Hinescu, M.E., and Ceafalan, L.C. (2018). Targeting CD36 as Biomarker for Metastasis Prognostic: How Far from Translation into Clinical Practice? Biomed Res Int 2018, 7801202.
Fan, J.G., and Farrell, G.C. (2009). Epidemiology of non-alcoholic fatty liver disease in China. J Hepatol 50, 204-210.
Fan, J.G., Kim, S.U., and Wong, V.W. (2017). New trends on obesity and NAFLD in Asia. J Hepatol 67, 862-873.
Ferlay, J., Shin, H.R., Bray, F., Forman, D., Mathers, C., and Parkin, D.M. (2010). Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127, 2893-2917.
Glass, A.S., and Dahm, R. (2004). The zebrafish as a model organism for eye development. Ophthalmic Res 36, 4-24.
Goessling, W., and Sadler, K.C. (2015). Zebrafish: an important tool for liver disease research. Gastroenterology 149, 1361-1377.
Greco, D., Kotronen, A., Westerbacka, J., Puig, O., Arkkila, P., Kiviluoto, T., Laitinen, S., Kolak, M., Fisher, R.M., Hamsten, A., et al. (2008). Gene expression in human NAFLD. Am J Physiol Gastrointest Liver Physiol 294, G1281-1287.
Green, C.J., and Hodson, L. (2014). The influence of dietary fat on liver fat accumulation. Nutrients 6, 5018-5033.
GreenWalt, D.E., Watt, K.W.K., So, O.Y., and Jiwani, N. (1990). PAS IV, an Integral Membrane Protein of Mammary Epithelial Cells, Is Related to Platelet and Endothelial Cell CD36 (GP 1V).
He, J., Lu, H., Zou, Q., and Luo, L. (2014). Regeneration of liver after extreme hepatocyte loss occurs mainly via biliary transdifferentiation in zebrafish. Gastroenterology 146, 789-800 e788.
Hill, J.O., Lin, D., Yakubu, F., and Peters, J.C. (1992). Development of dietary obesity in rats: influence of amount and composition of dietary fat. Int J Obes Relat Metab Disord 16, 321-333.
Hirano, K.-i., Kuwasako, T., Nakagawa-Toyama, Y., Janabi, M., Yamashita, S., and Matsuzawa, Y. (2003). Pathophysiology of Human Genetic CD36 Deficiency.
Hou, J., Wang, G., Wang, F., Cheng, J., Ren, H., Zhuang, H., Sun, J., Li, L., Li, J., Meng, Q., et al. (2017). Guideline of Prevention and Treatment for Chronic Hepatitis B (2015 Update). J Clin Transl Hepatol 5, 297-318.
Houston, D.K., Ding, J., Lee, J.S., Garcia, M., Kanaya, A.M., Tylavsky, F.A., Newman, A.B., Visser, M., Kritchevsky, S.B., and Health, A.B.C.S. (2011). Dietary fat and cholesterol and risk of cardiovascular disease in older adults: the Health ABC Study. Nutr Metab Cardiovasc Dis 21, 430-437.
Howe, K., Clark, M.D., Torroja, C.F., Torrance, J., Berthelot, C., Muffato, M., Collins, J.E., Humphray, S., McLaren, K., Matthews, L., et al. (2013). The zebrafish reference genome sequence and its relationship to the human genome. Nature 496, 498-503.
Ichimura, M., Kawase, M., Masuzumi, M., Sakaki, M., Nagata, Y., Tanaka, K., Suruga, K., Tamaru, S., Kato, S., Tsuneyama, K., et al. (2015). High-fat and high-cholesterol diet rapidly induces non-alcoholic steatohepatitis with advanced fibrosis in Sprague-Dawley rats. Hepatol Res 45, 458-469.
Imran, M., Sergent, O., Tete, A., Gallais, I., Chevanne, M., Lagadic-Gossmann, D., and Podechard, N. (2018). Membrane Remodeling as a Key Player of the Hepatotoxicity Induced by Co-Exposure to Benzo[a]pyrene and Ethanol of Obese Zebrafish Larvae. Biomolecules 8.
Inoue, M., Ohtake, T., Motomura, W., Takahashi, N., Hosoki, Y., Miyoshi, S., Suzuki, Y., Saito, H., Kohgo, Y., and Okumura, T. (2005). Increased expression of PPARgamma in high fat diet-induced liver steatosis in mice. Biochem Biophys Res Commun 336, 215-222.
Ito, M., Suzuki, J., Tsujioka, S., Sasaki, M., Gomori, A., Shirakura, T., Hirose, H., Ito, M., Ishihara, A., Iwaasa, H., et al. (2007). Longitudinal analysis of murine steatohepatitis model induced by chronic exposure to high-fat diet. Hepatol Res 37, 50-57.
Junga, Y.-J., Leea, K.-H., Choia, D.-W., Hana, C.J., Jeonga, S.H., Kima, K.-C., Ohc, J.-W., Parkb, T.-K., and Kima, C.-M. (2001). Reciprocal expressions of cyclin E and cyclin D1 in hepatocellular carcinoma.
Kayali, Z., and Schmidt, W.N. (2014). Finally sofosbuvir: an oral anti-HCV drug with wide performance capability. Pharmgenomics Pers Med 7, 387-398.
Koonen, D.P., Jacobs, R.L., Febbraio, M., Young, M.E., Soltys, C.L., Ong, H., Vance, D.E., and Dyck, J.R. (2007). Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity. Diabetes 56, 2863-2871.
Li, K.K.W., Ng, I.O.L., Fan, S.T., Albrecht, J.H., Yamashita, K., and Poon, R.Y.C. (2002). Activation of cyclin-dependent kinases CDC2 and CDK2 in hepatocellular carcinoma.
Liu, H.W., Tsai, Y.T., and Chang, S.J. (2014). Toona sinensis leaf extract inhibits lipid accumulation through up-regulation of genes involved in lipolysis and fatty acid oxidation in adipocytes. J Agric Food Chem 62, 5887-5896.
Llera-Moya, M.d.l., Rothblat, G.H., Connelly, M.A., Kellner-Weibel, G., Sakr, S.W., Phillips, M.C., and Williams, D.L. (1999). Scavenger receptor BI (SR-BI) mediates free cholesterol flux independently of HDL tethering to the cell surface.
Ma, S., Yang, J., Li, J., and Song, J. (2016). The clinical utility of the proliferating cell nuclear antigen expression in patients with hepatocellular carcinoma. Tumour Biol 37, 7405-7412.
Matsumoto, T., Terai, S., Oishi, T., Kuwashiro, S., Fujisawa, K., Yamamoto, N., Fujita, Y., Hamamoto, Y., Furutani-Seiki, M., Nishina, H., et al. (2010). Medaka as a model for human nonalcoholic steatohepatitis. Dis Model Mech 3, 431-440.
Memon, R.A., Fuller, J., Moser, A.H., Smith, P.J., Grunfeld, C., and Feingold, K.R. (1999). Regulation of Putative Fatty Acid Transporters and Acyl-CoA Synthetase in Liver and Adipose Tissue in o b/o b M i c e. DIABETES,.
Min, A.D., and Dienstag, J.L. (2007). Oral antivirals for chronic hepatitis B. Clin Liver Dis 11, 851-868, ix.
Miquilena-Colina, M.E., Lima-Cabello, E., Sanchez-Campos, S., Garcia-Mediavilla, M.V., Fernandez-Bermejo, M., Lozano-Rodriguez, T., Vargas-Castrillon, J., Buque, X., Ochoa, B., Aspichueta, P., et al. (2011). Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C. Gut 60, 1394-1402.
Mudbhary, R., Hoshida, Y., Chernyavskaya, Y., Jacob, V., Villanueva, A., Fiel, M.I., Chen, X., Kojima, K., Thung, S., Bronson, R.T., et al. (2014). UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma. Cancer Cell 25, 196-209.
Pepino, M.Y., Kuda, O., Samovski, D., and Abumrad, N.A. (2015). Structure-Function ofCD36 and Importance of Fatty Acid Signal Transduction in Fat Metabolism.
Reddy, J.K., and Rao, M.S. (2006). Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am J Physiol Gastrointest Liver Physiol 290, G852-858.
Roskoski, R., Jr. (2012). ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res 66, 105-143.
Sadler, K.C., Krahn, K.N., Gaur, N.A., and Ukomadu, C. (2007). Liver growth in the embryo and during liver regeneration in zebrafish requires the cell
cycle regulator, uhrf1. PNAS, 1570–1575.
Sanyal, A., Poklepovic, A., Moyneur, E., and Barghout, V. (2010). Population-based risk factors and resource utilization for HCC: US perspective. Curr Med Res Opin 26, 2183-2191.
Sapp, V., Gaffney, L., EauClaire, S.F., and Matthews, R.P. (2014). Fructose leads to hepatic steatosis in zebrafish that is reversed by mechanistic target of rapamycin (mTOR) inhibition. Hepatology 60, 1581-1592.
Schwenk, R.W., Luiken, J.J., Bonen, A., and Glatz, J.F. (2008). Regulation of sarcolemmal glucose and fatty acid transporters in cardiac disease. Cardiovasc Res 79, 249-258.
Scudellari, M. (2014). Drug development: try and try again.
Su, Z.L., Su, C.W., Huang, Y.L., Yang, W.Y., Sampurna, B.P., Ouchi, T., Lee, K.L., Wu, C.S., Wang, H.D., and Yuh, C.H. (2019). A Novel AURKA Mutant-Induced Early-Onset Severe Hepatocarcinogenesis Greater than Wild-Type via Activating Different Pathways in Zebrafish. Cancers (Basel) 11.
T, O., and GA., J. (1976). Platelet glycocalicin. I. Orientation of glycoproteins of the human platelet surface.
Tavares De Almeida, I., Cortez-Pinto, H., Fidalgo, G., Rodrigues, D., and Camilo, M.E. (2002). Plasma total and free fatty acids composition in human non-alcoholic steatohepatitis. Clinical Nutrition 21, 219-223.
Tu, H.C., Hsiao, Y.C., Yang, W.Y., Tsai, S.L., Lin, H.K., Liao, C.Y., Lu, J.W., Chou, Y.T., Wang, H.D., and Yuh, C.H. (2017). Up-regulation of golgi alpha-mannosidase IA and down-regulation of golgi alpha-mannosidase IC activates unfolded protein response during hepatocarcinogenesis. Hepatol Commun 1, 230-247.
Wong, R.J., Cheung, R., and Ahmed, A. (2014). Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology 59, 2188-2195.
Wu, C.X., Wang, X.Q., Chok, S.H., Man, K., Tsang, S.H.Y., Chan, A.C.Y., Ma, K.W., Xia, W., and Cheung, T.T. (2018). Blocking CDK1/PDK1/beta-Catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma. Theranostics 8, 3737-3750.
Xue, X.H., Shi, F.F., Chen, T., Wei, W., Zhou, X.M., and Chen, L.D. (2016). Inhibition of ERK1/2 improves lipid balance in rat macrophages via ABCA1/G1 and CD36. Mol Med Rep 13, 1533-1540.
Yanai, H., Chiba, H., Fujiwara, H., Morimoto, M., Abe, K., Yoshida, S., Takahashi, Y., Fuda, H., Hui, S.-P., Akita, H., et al. (2000). Phenotype-genotype Correlation in CD36 Deficiency Types I and II.
Yki-Jarvinen, H. (2010). Liver fat in the pathogenesis of insulin resistance and type 2 diabetes. Dig Dis 28, 203-209.
Younossi, Z.M., Koenig, A.B., Abdelatif, D., Fazel, Y., Henry, L., and Wymer, M. (2016). Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64, 73-84.
Zhang, W., Patil, S., Chauhan, B., Guo, S., Powell, D.R., Le, J., Klotsas, A., Matika, R., Xiao, X., Franks, R., et al. (2006). FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J Biol Chem 281, 10105-10117.
Zhou, L., Wang, Q., Yin, P., Xing, W., Wu, Z., Chen, S., Lu, X., Zhang, Y., Lin, X., and Xu, G. (2012). Serum metabolomics reveals the deregulation of fatty acids metabolism in hepatocellular carcinoma and chronic liver diseases. Anal Bioanal Chem 403, 203-213.
Zhou, X., Yin, Z., Guo, X., Hajjar, D.P., and Han, J. (2010). Inhibition of ERK1/2 and activation of liver X receptor synergistically induce macrophage ABCA1 expression and cholesterol efflux. J Biol Chem 285, 6316-6326.
Zhu, R.X., Seto, W.K., Lai, C.L., and Yuen, M.F. (2016). Epidemiology of Hepatocellular Carcinoma in the Asia-Pacific Region. Gut Liver 10, 332-339.