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Amelioration of non-alcoholic fatty liver disease with NPC1L1-targeted IgY or n-3 polyunsaturated fatty acids in mice.

Posted by on in 2017
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Bae JS1Park JM2Lee J1Oh BC1Jang SH3Lee YB4Han YM2Ock CY2Cha JY5Hahm KB6. 2017. Metabolism. 66:32-44. doi: 10.1016/j.metabol.2016.10.002. Epub 2016 Oct 11.

1Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea.
2CHA Cancer Prevention Research Center, CHA Bio Complex, CHA University, Seongnam, Gyunggi-do, 13488, Republic of Korea.
3Bioceltrand Co., Chuncheon, Gangwon-do, 200161, Republic of Korea.
4CHA 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.
5Department 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.
6CHA 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.

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.

KEYWORDS:

IgY; Liver fibrosis; N-3 PUFAs; NAFLD; NPC1L1

PMID:
 
27923447
 
DOI:
 
10.1016/j.metabol.2016.10.002
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