Amelioration of non-alcoholic fatty liver disease by targeting adhesion G protein-coupled receptor F1 (Adgrf1)
- Department of Chemistry and Chemical Engineering, Guangzhou University, China
- Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hong Kong
- Zhujiang Hospital, Southern Medical University, China
- Ionis Pharmaceuticals, United States
- Department of Medicine, University of Hong Kong, Hong Kong
- State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, China
- Department of Orthopaedics and Traumatology, Chinese University of Hong Kong, Hong Kong
- Hong Kong Polytechnic University, Shenzhen Research Institute, China
Figures
Figure 1
Adgrf1 is mainly expressed in the liver and its expression is downregulated after HFD treatment.
Eight-week-old male C57BL/6J mice were fed with either STC or HFD for 8 wk. (A) mRNA expression levels of Adgrf1 in different organs as determined by RT-qPCR analysis (n = 5). (B) Representative …
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Figure 1—source data 1
Adgrf1 is mainly expressed in the liver and its expression is downregulated after HFD treatment.
- https://cdn.elifesciences.org/articles/85131/elife-85131-fig1-data1-v1.zip
Figure 2 with 2 supplements
Overexpression of Adgrf1 in hepatocytes exaggerates metabolic dysregulation by HFD treatment.
Eight-week-old male C57BL/6J mice were infected with 3 × 1011 copies of rAAV encoding Adgrf1 (rAAV-Adgrf1, i.v.) or control (rAAV-GFP, i.v.) and received HFD feeding, respectively. (A) Schematic …
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Figure 2—source data 1
Overexpression of Adgrf1 in hepatocytes exaggerates metabolic dysregulation by HFD treatment.
- https://cdn.elifesciences.org/articles/85131/elife-85131-fig2-data1-v1.zip
Figure 2—figure supplement 1
Hepatic overexpression of Adgrf1 in STC-fed mice exhibits mild metabolic abnormalities.
Eight-week-old male C57BL/6J mice were infected with 3 × 1011 copies of AAV encoding Adgrf1 (rAAV-Adgrf1, i.v.) or control (rAAV-GFP, i.v.) and fed with STC diet. (A) Schematic illustration of viral …
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Figure 2—figure supplement 1—source data 1
Hepatic overexpression of Adgrf1 in STC-fed mice exhibits mild metabolic abnormalities.
- https://cdn.elifesciences.org/articles/85131/elife-85131-fig2-figsupp1-data1-v1.zip
Figure 2—figure supplement 2
Overexpression of Adgrf1 did not interfere adipose tissues and other metabolic phenotypes.
(A) mRNA expression levels of Adgrf1 in SWAT, EWAT, and BAT as determined by RT-qPCR analysis. (B) The average daily pedestrian locomotion, (C) average distance in cage locomotion, (D) average …
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Figure 2—figure supplement 2—source data 1
Overexpression of Adgrf1 did not interfere adipose tissues and other metabolic phenotypes.
- https://cdn.elifesciences.org/articles/85131/elife-85131-fig2-figsupp2-data1-v1.zip
Figure 3 with 1 supplement
Deletion of hepatic Adgrf1 protects against diet-induced glucose intolerance in Adgrf1 overexpress mice.
Eight-week-old male C57BL/6J mice were infected with either 3 × 1011 copies of rAAV encoding Adgrf1 (rAAV-Adgrf1, i.v.) or control (rAAV-GFP, i.v.) and two different sequences of Adgrf1 ASO (ASO1-Adg…
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Figure 3—source data 1
Deletion of hepatic Adgrf1 protects against diet-induced glucose intolerance in Adgrf1 overexpress mice.
- https://cdn.elifesciences.org/articles/85131/elife-85131-fig3-data1-v1.zip
Figure 3—figure supplement 1
Hepatic knockdown of Adgrf1 in STC-fed mice does not exhibit metabolic abnormalities.
Eight-week-old male C57BL/6J mice were infected with two different sequences of Adgrf1 antisense oligonucleotides (ASO1-Adgrf1, ASO2-Adgrf1, 5 mg/kg, one dose per week, s.c.) or scrambled control …
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Figure 3—figure supplement 1—source data 1
Hepatic knockdown of Adgrf1 in STC-fed mice does not exhibit metabolic abnormalities.
- https://cdn.elifesciences.org/articles/85131/elife-85131-fig3-figsupp1-data1-v1.zip
Figure 4
Upregulation of hepatic Adgrf1 exaggerates liver steatosis in HFD-fed mice while downregulation of hepatic Adgrf1 protects mice from diet-induced liver lipid accumulation.
Eight-week-old male C57BL/6J mice were infected with either 3 × 1011 copies of rAAV encoding Adgrf1 (rAAV-Adgrf1, i.v.) or control (rAAV-NC, i.v.) and two different sequences of Adgrf1 antisense …
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Figure 4—source data 1
Upregulation of hepatic Adgrf1 exaggerates liver steatosis in HFD-fed mice while downregulation of hepatic Adgrf1 protects mice from diet-induced liver lipid accumulation.
- https://cdn.elifesciences.org/articles/85131/elife-85131-fig4-data1-v1.zip
Figure 5
Adgrf1 is a major regulator of hepatic lipid metabolism.
Eight-week-old male C57BL/6J mice were infected with either 3 × 1011 copies of rAAV encoding Adgrf1 (rAAV-Adgrf1, i.v.) or control (rAAV-NC, i.v.) and two Adgrf1 antisense oligonucleotides (ASO1-Adgr…
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Figure 5—source data 1
Adgrf1 is a major regulator of hepatic lipid metabolism.
- https://cdn.elifesciences.org/articles/85131/elife-85131-fig5-data1-v1.zip
Figure 6
Scd1 expression is regulated by Adgrf1 in primary hepatocytes.
Primary hepatocytes were isolated from 8-week-old male C57BL/6J mice with STC. (A) Primary hepatocytes were infected with either adenoviral vector expressing Adgrf1 (ADV-Adgrf1) or control …
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Figure 6—source data 1
Scd1 expression is regulated by Adgrf1 in primary hepatocytes.
- https://cdn.elifesciences.org/articles/85131/elife-85131-fig6-data1-v1.zip
Figure 7
Inhibition of Scd1 alleviates the glucose impairment in mice with hepatic Adgrf1 overexpression.
Eight-week-old male C57BL/6J mice were infected with either 3 × 1011 copies of rAAV encoding Adgrf1 (rAAV-Adgrf1, i.v.) or control (rAAV-GFP, i.v.) and Scd1 inhibitor (MK8245, 10 mg/kg/week, p.o.) …
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Figure 7—source data 1
Inhibition of Scd1 alleviates the glucose impairment in mice with hepatic Adgrf1 overexpression.
- https://cdn.elifesciences.org/articles/85131/elife-85131-fig7-data1-v1.zip
Figure 8
Inhibition of hepatic Scd1 partially alleviates the severity of hepatic steatosis in Adgrf1 overexpression mice.
Eight-week-old male C57BL/6N mice were infected with either 3 × 1011 copies of rAAV encoding Adgrf1 (rAAV-Adgrf1, i.v.) or control (rAAV-GFP, i.v.) and administered with Scd1 inhibitor (MK8245, 10 …
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Figure 8—source data 1
Inhibition of hepatic Scd1 partially alleviates the severity of hepatic steatosis in Adgrf1 overexpression mice.
- https://cdn.elifesciences.org/articles/85131/elife-85131-fig8-data1-v1.zip
Figure 9
Hepatic expression of ADGRF1 is upregulated in obese patients with hepatic steatosis when compared to those with normal liver morphology, which is positively associated with hepatic SCD1 expression level.
NAFLD patients have higher hepatic expression of ADGRF1 accompanied with increased mRNA Scd1 expression. (A) Normalized Log2 mRNA expression of ADGRF1 in lean people without NAFLD (n = 12), obese …
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Figure 9—source data 1
Hepatic expression of ADGRF1 is upregulated in obese patients with hepatic steatosis when compared to those with normal liver morphology, which is positively associated with hepatic SCD1 expression level.
- https://cdn.elifesciences.org/articles/85131/elife-85131-fig9-data1-v1.zip
Tables
Author response table 1
| Sequence | GalNac position | Position of 2’ sugar modification | |
|---|---|---|---|
| ASO1 | AGGAAAATTTCGCTGA | 5’-end | 3*-10-3* |
| ASO2 | GAATTTTAGGACTTGC | 5’-end | 3*-10-3* |
Additional files
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MDAR checklist
- https://cdn.elifesciences.org/articles/85131/elife-85131-mdarchecklist1-v1.pdf
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Supplementary file 1
List of primary antibodies.
- https://cdn.elifesciences.org/articles/85131/elife-85131-supp1-v1.zip
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Supplementary file 2
List of primers used for RT-qPCR.
- https://cdn.elifesciences.org/articles/85131/elife-85131-supp2-v1.zip
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Supplementary file 3
Expression of GPCRs in the liver of mice fed with either STC or HFD diet for 8 weeks by gene expression microarray analysis.
- https://cdn.elifesciences.org/articles/85131/elife-85131-supp3-v1.zip
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Supplementary file 4
Expression of lipogenic genes in the liver of mice fed with either STC or HFD diet for 8 weeks by gene expression microarray analysis.
- https://cdn.elifesciences.org/articles/85131/elife-85131-supp4-v1.zip
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Supplementary file 5
Raw data for baseline characteristics of study cohorts.
- https://cdn.elifesciences.org/articles/85131/elife-85131-supp5-v1.zip
