Association between betatrophin/ANGPTL8 and non-alcoholic fatty liver disease: Animal and human studies

Yong Ho Lee, Sang Guk Lee, Chan Joo Lee, Soo Hyun Kim, Young Mi Song, Mi Ra Yoon, Byung Hun Jeon, Jae Hyuk Lee, Byung Wan Lee, Eun Seok Kang, Hyun Chul Lee, Bong Soo Cha

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Betatrophin/angiopoietin-like protein 8 (ANGPTL8) is a liver-secreted protein recently identified as a potent stimulator of beta cell proliferation in mice. However, it is unclear how betatrophin is regulated in humans with non-alcoholic fatty liver disease (NAFLD). We investigated the role of betatrophin in mice and in humans with and without NAFLD. Serum betatrophin levels were examined by ELISA in 164 subjects, including 96 patients with NAFLD. Levels were significantly elevated in subjects with NAFLD compared with controls (1.301 ± 0.617 vs. 0.900 ± 0.574 μg/L, P < 0.001), even after stratification by diabetic or obesity status. Circulating betatrophin positively correlated with obesity or glycemic indices, liver enzyme profiles, and NAFLD status, and was confirmed by multivariate regression analyses (β = 0.195, P = 0.040). However, when including insulin resistance index in the model, the significant association between betatrophin level and NAFLD was diminished due to a mediation effect of insulin resistance on this relationship. Palmitate or tunicamycin increased betatrophin expression in HepG2 cells, while a chemical chaperone blocked its induction. Hepatic expression of betatrophin was elevated in mice with NAFLD including db/db or ob/ob mice and mice with a high-fat or methionine-choline deficient diet. In conclusion, circulating betatrophin was increased in mice and humans with NAFLD and its expression was induced by endoplasmic reticulum stress in hepatocytes (Clinical trial no. NCT02285218).

Original languageEnglish
Article number24013
JournalScientific reports
Volume6
DOIs
Publication statusPublished - 2016 Apr 5

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Angiopoietins
Proteins
Insulin Resistance
Liver
Obesity
Glycemic Index
Tunicamycin
Endoplasmic Reticulum Stress
Non-alcoholic Fatty Liver Disease
Palmitates
Hep G2 Cells
Choline
Methionine
Hepatocytes
Multivariate Analysis
Enzyme-Linked Immunosorbent Assay
Fats
Regression Analysis
Cell Proliferation
Clinical Trials

All Science Journal Classification (ASJC) codes

  • General

Cite this

Lee, Y. H., Lee, S. G., Lee, C. J., Kim, S. H., Song, Y. M., Yoon, M. R., ... Cha, B. S. (2016). Association between betatrophin/ANGPTL8 and non-alcoholic fatty liver disease: Animal and human studies. Scientific reports, 6, [24013]. https://doi.org/10.1038/srep24013
Lee, Yong Ho ; Lee, Sang Guk ; Lee, Chan Joo ; Kim, Soo Hyun ; Song, Young Mi ; Yoon, Mi Ra ; Jeon, Byung Hun ; Lee, Jae Hyuk ; Lee, Byung Wan ; Kang, Eun Seok ; Lee, Hyun Chul ; Cha, Bong Soo. / Association between betatrophin/ANGPTL8 and non-alcoholic fatty liver disease : Animal and human studies. In: Scientific reports. 2016 ; Vol. 6.
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abstract = "Betatrophin/angiopoietin-like protein 8 (ANGPTL8) is a liver-secreted protein recently identified as a potent stimulator of beta cell proliferation in mice. However, it is unclear how betatrophin is regulated in humans with non-alcoholic fatty liver disease (NAFLD). We investigated the role of betatrophin in mice and in humans with and without NAFLD. Serum betatrophin levels were examined by ELISA in 164 subjects, including 96 patients with NAFLD. Levels were significantly elevated in subjects with NAFLD compared with controls (1.301 ± 0.617 vs. 0.900 ± 0.574 μg/L, P < 0.001), even after stratification by diabetic or obesity status. Circulating betatrophin positively correlated with obesity or glycemic indices, liver enzyme profiles, and NAFLD status, and was confirmed by multivariate regression analyses (β = 0.195, P = 0.040). However, when including insulin resistance index in the model, the significant association between betatrophin level and NAFLD was diminished due to a mediation effect of insulin resistance on this relationship. Palmitate or tunicamycin increased betatrophin expression in HepG2 cells, while a chemical chaperone blocked its induction. Hepatic expression of betatrophin was elevated in mice with NAFLD including db/db or ob/ob mice and mice with a high-fat or methionine-choline deficient diet. In conclusion, circulating betatrophin was increased in mice and humans with NAFLD and its expression was induced by endoplasmic reticulum stress in hepatocytes (Clinical trial no. NCT02285218).",
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Lee, YH, Lee, SG, Lee, CJ, Kim, SH, Song, YM, Yoon, MR, Jeon, BH, Lee, JH, Lee, BW, Kang, ES, Lee, HC & Cha, BS 2016, 'Association between betatrophin/ANGPTL8 and non-alcoholic fatty liver disease: Animal and human studies', Scientific reports, vol. 6, 24013. https://doi.org/10.1038/srep24013

Association between betatrophin/ANGPTL8 and non-alcoholic fatty liver disease : Animal and human studies. / Lee, Yong Ho; Lee, Sang Guk; Lee, Chan Joo; Kim, Soo Hyun; Song, Young Mi; Yoon, Mi Ra; Jeon, Byung Hun; Lee, Jae Hyuk; Lee, Byung Wan; Kang, Eun Seok; Lee, Hyun Chul; Cha, Bong Soo.

In: Scientific reports, Vol. 6, 24013, 05.04.2016.

Research output: Contribution to journalArticle

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T1 - Association between betatrophin/ANGPTL8 and non-alcoholic fatty liver disease

T2 - Animal and human studies

AU - Lee, Yong Ho

AU - Lee, Sang Guk

AU - Lee, Chan Joo

AU - Kim, Soo Hyun

AU - Song, Young Mi

AU - Yoon, Mi Ra

AU - Jeon, Byung Hun

AU - Lee, Jae Hyuk

AU - Lee, Byung Wan

AU - Kang, Eun Seok

AU - Lee, Hyun Chul

AU - Cha, Bong Soo

PY - 2016/4/5

Y1 - 2016/4/5

N2 - Betatrophin/angiopoietin-like protein 8 (ANGPTL8) is a liver-secreted protein recently identified as a potent stimulator of beta cell proliferation in mice. However, it is unclear how betatrophin is regulated in humans with non-alcoholic fatty liver disease (NAFLD). We investigated the role of betatrophin in mice and in humans with and without NAFLD. Serum betatrophin levels were examined by ELISA in 164 subjects, including 96 patients with NAFLD. Levels were significantly elevated in subjects with NAFLD compared with controls (1.301 ± 0.617 vs. 0.900 ± 0.574 μg/L, P < 0.001), even after stratification by diabetic or obesity status. Circulating betatrophin positively correlated with obesity or glycemic indices, liver enzyme profiles, and NAFLD status, and was confirmed by multivariate regression analyses (β = 0.195, P = 0.040). However, when including insulin resistance index in the model, the significant association between betatrophin level and NAFLD was diminished due to a mediation effect of insulin resistance on this relationship. Palmitate or tunicamycin increased betatrophin expression in HepG2 cells, while a chemical chaperone blocked its induction. Hepatic expression of betatrophin was elevated in mice with NAFLD including db/db or ob/ob mice and mice with a high-fat or methionine-choline deficient diet. In conclusion, circulating betatrophin was increased in mice and humans with NAFLD and its expression was induced by endoplasmic reticulum stress in hepatocytes (Clinical trial no. NCT02285218).

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