PMID- 31684957
OWN - NLM
STAT- MEDLINE
DCOM- 20200406
LR  - 20220110
IS  - 1476-511X (Electronic)
IS  - 1476-511X (Linking)
VI  - 18
IP  - 1
DP  - 2019 Nov 4
TI  - Hepatitis C virus nonstructural protein 5A perturbs lipid metabolism by 
      modulating AMPK/SREBP-1c signaling.
PG  - 191
LID - 10.1186/s12944-019-1136-y [doi]
LID - 191
AB  - BACKGROUND: Steatosis is an important clinical manifestation associated with 
      chronic hepatitis C virus (HCV) infection. AMP-activated protein kinase (AMPK), a 
      major mediator of lipid metabolism, regulates HCV-associated hepatic steatosis, 
      but the underlying mechanisms remain obscure. Here we investigated the mechanism 
      of HCV nonstructural protein 5A (NS5A)-induced lipid accumulation by the 
      AMPK/SREBP-1c pathway. METHODS: We generated model mice by injecting recombinant 
      lentiviral particles expressing the NS5A protein (genotype 3a) via the tail vein. 
      The serum levels of alanine aminotransferase (ALT), free fatty acids (FFAs) and 
      triglycerides (TG) were examined. H&E and Oil Red O staining were used to examine 
      lipid droplets. Immunohistochemistry staining, quantitative real-time PCR and 
      Western blotting were used to determine the expression of lipogenic genes. 
      RESULTS: Our results showed that the serum levels of ALT, FFAs and TG, as well as 
      the accumulation of hepatic lipid droplets, were increased significantly in mice 
      infected with NS5A-expressing lentiviral particles. NS5A inhibited AMPK 
      phosphorylation and increased the expression levels of sterol regulatory element 
      binding protein-1c (SREBP-1c), acetyl-coenzyme A carboxylase 1 (ACC1) and fatty 
      acid synthase (FASN) in vivo and in vitro. Further investigation revealed that 
      pharmacological activation or ectopic expression of AMPK neutralized the 
      upregulation of SREBP-1c, ACC1 and FASN, and ameliorated hepatic lipid 
      accumulation induced by NS5A. Ectopic expression of SREBP-1c enhanced 
      NS5A-induced hepatic lipid accumulation, which was dramatically reversed by 
      pharmacological activation of AMPK. CONCLUSIONS: Collectively, we demonstrate 
      that NS5A induces hepatic lipid accumulation via the AMPK/SREBP-1c pathway.
FAU - Meng, Ziyu
AU  - Meng Z
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & 
      Tianjin Institute of Endocrinology, Tianjin, 300134, China.
FAU - Liu, Qiang
AU  - Liu Q
AD  - Vaccine and Infectious Disease Organization-International Vaccine Centre 
      (VIDO-InterVac), School of Public Health Vaccinology and Immunotherapeutics, 
      Department of Veterinary Microbiology, University of Saskatchewan, S7N5E3, 
      Saskatoon, Canada.
FAU - Sun, Fujun
AU  - Sun F
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & 
      Tianjin Institute of Endocrinology, Tianjin, 300134, China.
FAU - Qiao, Ling
AU  - Qiao L
AUID- ORCID: 0000-0003-1160-9738
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & 
      Tianjin Institute of Endocrinology, Tianjin, 300134, China. 
      qiaoling@tijmu.edu.cn.
LA  - eng
GR  - 81370955/National Natural Science Foundation of China/
GR  - 31800722/National Natural Science Foundation of China/
GR  - 81800767/National Natural Science Foundation of China/
GR  - 19JCQNJC11400/Natural Science Foundation of Tianjin City/
GR  - 18JCYBJC25500/Natural Science Foundation of Tianjin City/
GR  - 2017DX06;2017RC02/Scientific Research Funding of Tianjin Medical University Chu 
      Hsien-I Memorial Hospital/
PT  - Journal Article
DEP - 20191104
PL  - England
TA  - Lipids Health Dis
JT  - Lipids in health and disease
JID - 101147696
RN  - 0 (Sterol Regulatory Element Binding Protein 1)
RN  - 0 (Viral Nonstructural Proteins)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - EC 2.7.7.48 (NS-5 protein, hepatitis C virus)
RN  - EC 6.4.1.2 (ACC1 protein, mouse)
RN  - EC 6.4.1.2 (Acetyl-CoA Carboxylase)
SB  - IM
MH  - AMP-Activated Protein Kinases/genetics/*metabolism
MH  - Acetyl-CoA Carboxylase/genetics/metabolism
MH  - Animals
MH  - Blotting, Western
MH  - Cell Line
MH  - Female
MH  - Hep G2 Cells
MH  - Humans
MH  - Immunohistochemistry
MH  - Lipid Metabolism/genetics/physiology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Real-Time Polymerase Chain Reaction
MH  - Sterol Regulatory Element Binding Protein 1/genetics/*metabolism
MH  - Viral Nonstructural Proteins/genetics/*metabolism
PMC - PMC6829953
OTO - NOTNLM
OT  - AMP-activated protein kinase
OT  - Hepatic steatosis
OT  - Hepatitis C virus
OT  - Nonstructural protein 5A
OT  - Sterol regulatory element-binding protein-1c
COIS- The authors declare that they have no competing interests.
EDAT- 2019/11/07 06:00
MHDA- 2020/04/09 06:00
PMCR- 2019/11/04
CRDT- 2019/11/06 06:00
PHST- 2019/09/05 00:00 [received]
PHST- 2019/10/20 00:00 [accepted]
PHST- 2019/11/06 06:00 [entrez]
PHST- 2019/11/07 06:00 [pubmed]
PHST- 2020/04/09 06:00 [medline]
PHST- 2019/11/04 00:00 [pmc-release]
AID - 10.1186/s12944-019-1136-y [pii]
AID - 1136 [pii]
AID - 10.1186/s12944-019-1136-y [doi]
PST - epublish
SO  - Lipids Health Dis. 2019 Nov 4;18(1):191. doi: 10.1186/s12944-019-1136-y.