title: Amelioration of non-alcoholic fatty liver disease with NPC1L1-targeted IgY or n-3 polyunsaturated fatty acids in mice.
abstract: Patients with non-alcoholic fatty liver disease (NAFLD) have an increased risk for progression to hepatocellular carcinoma in addition to comorbidities such as cardiovascular and serious metabolic diseases; however, the current therapeutic options are limited. Based on our previous report that omega-3 polyunsaturated fatty acids (n-3 PUFAs) can significantly ameliorate high fat diet (HFD)-induced NAFLD, we explored the therapeutic efficacy of n-3 PUFAs and N-IgY, which is a chicken egg yolk-derived IgY specific for the Niemann-Pick C1-Like 1 (NPC1L1) cholesterol transporter, on NAFLD in mice. We generated N-IgY and confirmed its efficient cholesterol transport-blocking activity in HepG2 and Caco-2 cells, which was comparable to the effect of ezetimibe (EZM). C57BL/6 wild type and fat-1 transgenic mice, capable of producing n-3 PUFAs, were fed a high fat diet (HFD) alone or supplemented with N-IgY. Endogenously synthesized n-3 PUFAs combined with N-IgY led to significant decreases in hepatic steatosis, fibrosis, and inflammation (p<0.01). The combination of N-IgY and n-3 PUFAs resulted in significant upregulation of genes involved in cholesterol uptake (LDLR), reverse cholesterol transport (ABCG5/ABCG8), and bile acid metabolism (CYP7A1). Moreover, fat-1 transgenic mice treated with N-IgY showed significant downregulation of genes involved in cholesterol-induced hepatic stellate cell activation (Tgfb1, Tlr4, Col1a1, Col1a2, and Timp2). Collectively, these data suggest that n-3 PUFAs and N-IgY, alone or in combination, represent a promising treatment strategy to prevent HFD-induced fatty liver through the activation cholesterol catabolism to bile acids and by decreasing cholesterol-induced fibrosis.
authors.affiliation: Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea.
authors.forename: Jin-Sik
authors.initials: JS
authors.lastname: Bae
authors.affiliation: CHA Cancer Prevention Research Center, CHA Bio Complex, CHA University, Seongnam, Gyunggi-do, 13488, Republic of Korea.
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Park
authors.affiliation: Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea.
authors.forename: Junghoon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea.
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Oh
authors.affiliation: Bioceltrand Co., Chuncheon, Gangwon-do, 200161, Republic of Korea.
authors.forename: Sang-Ho
authors.initials: SH
authors.lastname: Jang
authors.affiliation: CHA Cancer Prevention Research Center, CHA Bio Complex, CHA University, Seongnam, Gyunggi-do, 13488, Republic of Korea; Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, Gyunggi-do, 13496, Republic of Korea.
authors.forename: Yun Bin
authors.initials: YB
authors.lastname: Lee
authors.affiliation: CHA Cancer Prevention Research Center, CHA Bio Complex, CHA University, Seongnam, Gyunggi-do, 13488, Republic of Korea.
authors.forename: Young-Min
authors.initials: YM
authors.lastname: Han
authors.affiliation: CHA Cancer Prevention Research Center, CHA Bio Complex, CHA University, Seongnam, Gyunggi-do, 13488, Republic of Korea.
authors.forename: Chan-Young
authors.initials: CY
authors.lastname: Ock
authors.affiliation: Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea; Gachon Medical Research Institute, Gil Hospital, Incheon 21565, Republic of Korea. Electronic address: jycha1014@gachon.ac.kr.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Cha
authors.affiliation: CHA Cancer Prevention Research Center, CHA Bio Complex, CHA University, Seongnam, Gyunggi-do, 13488, Republic of Korea; Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, Gyunggi-do, 13496, Republic of Korea. Electronic address: hahmkb@cha.ac.kr.
authors.forename: Ki-Baik
authors.initials: KB
authors.lastname: Hahm
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D044943:Fatty Acid Desaturases / Q000235:genetics; D015525:Fatty Acids, Omega-3 / Q000627:therapeutic use*; D005231:Fatty Acids, Unsaturated / Q000627:therapeutic use; D056945:Hep G2 Cells; D006801:Humans; D007136:Immunoglobulins / Q000627:therapeutic use*; D007167:Immunotherapy; D008297:Male; D026901:Membrane Transport Proteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy / Q000379:methods; D065626:Non-alcoholic Fatty Liver Disease / Q000178:diet therapy / Q000235:genetics / Q000473:pathology / Q000628:therapy*
chemical_list: D029742:Caenorhabditis elegans Proteins; D015525:Fatty Acids, Omega-3; D005231:Fatty Acids, Unsaturated; C016512:IgY; D007136:Immunoglobulins; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; C466741:fat-1 protein, C elegans; D044943:Fatty Acid Desaturases
keywords: IgY; Liver fibrosis; N-3 PUFAs; NAFLD; NPC1L1