Coagulation Factor VII Fine-tunes Hepatic Steatosis by Blocking AKT-CD36-Mediated Fatty Acid Uptake
© 2024 by the American Diabetes Association..
Nonalcoholic fatty liver disease (NAFLD) is considered a risk factor for cardiovascular and cerebrovascular disease owing to its close association with coagulant disturbances. However, the precise biological functions and mechanisms that connect coagulation factors to NAFLD pathology remain inadequately understood. Herein, with unbiased bioinformatics analyses followed by functional testing, we demonstrate that hepatic expression of coagulation factor VII (FVII) decreases in patients and mice with NAFLD/nonalcoholic steatohepatitis (NASH). By using adenovirus-mediated F7-knockdown and hepatocyte-specific F7-knockout mouse models, our mechanistic investigations unveil a noncoagulant function of hepatic FVII in mitigating lipid accumulation and lipotoxicity. This protective effect is achieved through the suppression of fatty acid uptake, orchestrated via the AKT-CD36 pathway. Interestingly, intracellular FVII directly interacts with AKT and PP2A, thereby promoting their association and triggering the dephosphorylation of AKT. Therapeutic intervention through adenovirus-mediated liver-specific overexpression of F7 results in noteworthy improvements in liver steatosis, inflammation, injury, and fibrosis in severely afflicted NAFLD mice. In conclusion, our findings highlight coagulation factor FVII as a critical regulator of hepatic steatosis and a potential target for the treatment of NAFLD and NASH.
ARTICLE HIGHLIGHTS:.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:73 |
|---|---|
| Enthalten in: |
Diabetes - 73(2024), 5 vom: 01. Apr., Seite 682-700 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Zhang, Yao [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
9001-25-6 |
|---|
| Anmerkungen: |
Date Completed 22.04.2024 Date Revised 22.04.2024 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.2337/db23-0814 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM368846288 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM368846288 | ||
| 003 | DE-627 | ||
| 005 | 20240422232133.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240229s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.2337/db23-0814 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1383.xml |
| 035 | |a (DE-627)NLM368846288 | ||
| 035 | |a (NLM)38394642 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Zhang, Yao |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Coagulation Factor VII Fine-tunes Hepatic Steatosis by Blocking AKT-CD36-Mediated Fatty Acid Uptake |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 22.04.2024 | ||
| 500 | |a Date Revised 22.04.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024 by the American Diabetes Association. | ||
| 520 | |a Nonalcoholic fatty liver disease (NAFLD) is considered a risk factor for cardiovascular and cerebrovascular disease owing to its close association with coagulant disturbances. However, the precise biological functions and mechanisms that connect coagulation factors to NAFLD pathology remain inadequately understood. Herein, with unbiased bioinformatics analyses followed by functional testing, we demonstrate that hepatic expression of coagulation factor VII (FVII) decreases in patients and mice with NAFLD/nonalcoholic steatohepatitis (NASH). By using adenovirus-mediated F7-knockdown and hepatocyte-specific F7-knockout mouse models, our mechanistic investigations unveil a noncoagulant function of hepatic FVII in mitigating lipid accumulation and lipotoxicity. This protective effect is achieved through the suppression of fatty acid uptake, orchestrated via the AKT-CD36 pathway. Interestingly, intracellular FVII directly interacts with AKT and PP2A, thereby promoting their association and triggering the dephosphorylation of AKT. Therapeutic intervention through adenovirus-mediated liver-specific overexpression of F7 results in noteworthy improvements in liver steatosis, inflammation, injury, and fibrosis in severely afflicted NAFLD mice. In conclusion, our findings highlight coagulation factor FVII as a critical regulator of hepatic steatosis and a potential target for the treatment of NAFLD and NASH | ||
| 520 | |a ARTICLE HIGHLIGHTS: | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Proto-Oncogene Proteins c-akt |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Factor VII |2 NLM | |
| 650 | 7 | |a 9001-25-6 |2 NLM | |
| 650 | 7 | |a Fatty Acids |2 NLM | |
| 700 | 1 | |a Jiang, Quanxin |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Xingxing |e verfasserin |4 aut | |
| 700 | 1 | |a Qian, Qiqi |e verfasserin |4 aut | |
| 700 | 1 | |a Xiong, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Chuchu |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Junting |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Ning |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Peihui |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Sijia |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Qian |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Yanmei |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Xuemei |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Junli |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Suzhen |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Diabetes |d 1952 |g 73(2024), 5 vom: 01. Apr., Seite 682-700 |w (DE-627)NLM000060011 |x 1939-327X |7 nnns |
| 773 | 1 | 8 | |g volume:73 |g year:2024 |g number:5 |g day:01 |g month:04 |g pages:682-700 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.2337/db23-0814 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 73 |j 2024 |e 5 |b 01 |c 04 |h 682-700 | ||