PMID- 36881564
OWN - NLM
STAT- MEDLINE
DCOM- 20230811
LR  - 20230811
IS  - 1522-1547 (Electronic)
IS  - 0193-1857 (Print)
IS  - 0193-1857 (Linking)
VI  - 324
IP  - 5
DP  - 2023 May 1
TI  - Myeloid-specific fatty acid transport protein 4 deficiency induces a 
      sex-dimorphic susceptibility for nonalcoholic steatohepatitis in mice fed a 
      high-fat, high-cholesterol diet.
PG  - G389-G403
LID - 10.1152/ajpgi.00181.2022 [doi]
AB  - Newborns with FATP4 mutations exhibit ichthyosis prematurity syndrome (IPS), and 
      adult patients show skin hyperkeratosis, allergies, and eosinophilia. We have 
      previously shown that the polarization of macrophages is altered by FATP4 
      deficiency; however, the role of myeloid FATP4 in the pathogenesis of 
      nonalcoholic steatohepatitis (NASH) is not known. We herein phenotyped 
      myeloid-specific Fatp4-deficient (Fatp4(M-/-)) mice under chow and high-fat, 
      high-cholesterol (HFHC) diet. Bone-marrow-derived macrophages (BMDMs) from 
      Fatp4(M-/-) mice showed significant reduction in cellular sphingolipids in males 
      and females, and additionally phospholipids in females. BMDMs and Kupffer cells 
      from Fatp4(M-/-) mice exhibited increased LPS-dependent activation of 
      proinflammatory cytokines and transcription factors PPARgamma, CEBPalpha, and p-FoxO1. 
      Correspondingly, these mutants under chow diet displayed thrombocytopenia, 
      splenomegaly, and elevated liver enzymes. After HFHC feeding, Fatp4(M-/-) mice 
      showed increased MCP-1 expression in livers and subcutaneous fat. Plasma MCP-1, 
      IL4, and IL13 levels were elevated in male and female mutants, and female mutants 
      additionally showed elevation of IL5 and IL6. After HFHC feeding, male mutants 
      showed an increase in hepatic steatosis and inflammation, whereas female mutants 
      showed a greater severity in hepatic fibrosis associated with immune cell 
      infiltration. Thus, myeloid-FATP4 deficiency led to steatotic and inflammatory 
      NASH in males and females, respectively. Our work offers some implications for 
      patients with FATP4 mutations and also highlights considerations in the design of 
      sex-targeted therapies for NASH treatment.NEW & NOTEWORTHY FATP4 deficiency in 
      BMDMs and Kupffer cells led to increased proinflammatory response. Fatp4(M-/-) 
      mice displayed thrombocytopenia, splenomegaly, and elevated liver enzymes. In 
      response to HFHC feeding, male mutants were prone to hepatic steatosis, whereas 
      female mutants showed exaggerated fibrosis. Our study provides insights into a 
      sex-dimorphic susceptibility to NASH by myeloid-FATP4 deficiency.
FAU - Gocebe, Deniz
AU  - Gocebe D
AD  - Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, 
      Germany.
FAU - Jansakun, Chutima
AU  - Jansakun C
AUID- ORCID: 0000-0002-7892-4436
AD  - Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, 
      Germany.
AD  - School of Allied Health Sciences, Walailak University, Nakhonsrithammarat, 
      Thailand.
FAU - Zhang, Yuling
AU  - Zhang Y
AUID- ORCID: 0000-0001-8956-2808
AD  - Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, 
      Germany.
FAU - Staffer, Simone
AU  - Staffer S
AD  - Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, 
      Germany.
FAU - Tuma-Kellner, Sabine
AU  - Tuma-Kellner S
AD  - Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, 
      Germany.
FAU - Altamura, Sandro
AU  - Altamura S
AUID- ORCID: 0000-0002-6781-1073
AD  - Department of Pediatric Oncology, Hematology and Immunology, University Hospital 
      Heidelberg, Heidelberg, Germany.
FAU - Muckenthaler, Martina U
AU  - Muckenthaler MU
AD  - Department of Pediatric Oncology, Hematology and Immunology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - Translational Lung Research Center Heidelberg, German Center for Lung Research 
      (DZL), German Centre for Cardiovascular Research, Partner Site, University of 
      Heidelberg, Heidelberg, Germany.
FAU - Merle, Uta
AU  - Merle U
AUID- ORCID: 0000-0003-1386-3350
AD  - Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, 
      Germany.
FAU - Herrmann, Thomas
AU  - Herrmann T
AD  - Westkuesten Hospital, Heide, Germany.
FAU - Chamulitrat, Walee
AU  - Chamulitrat W
AUID- ORCID: 0000-0002-5999-7664
AD  - Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, 
      Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230307
PL  - United States
TA  - Am J Physiol Gastrointest Liver Physiol
JT  - American journal of physiology. Gastrointestinal and liver physiology
JID - 100901227
RN  - 97C5T2UQ7J (Cholesterol)
RN  - 0 (Fatty Acid Transport Proteins)
RN  - 0 (Slc27a4 protein, mouse)
SB  - IM
MH  - Animals
MH  - Female
MH  - Male
MH  - Mice
MH  - Cholesterol/metabolism
MH  - Diet, High-Fat
MH  - *Fatty Acid Transport Proteins/genetics/metabolism
MH  - Liver/metabolism
MH  - *Non-alcoholic Fatty Liver Disease/genetics/complications
MH  - Splenomegaly/complications/metabolism/pathology
PMC - PMC10085558
OTO - NOTNLM
OT  - fatty acid transport proteins
OT  - high-cholesterol diets
OT  - high-fat
OT  - macrophage polarization
OT  - monocyte chemoattractant protein-1
OT  - nonalcoholic steatohepatitis
COIS- No conflicts of interest, financial or otherwise, are declared by the authors.
EDAT- 2023/03/08 06:00
MHDA- 2023/04/06 10:16
PMCR- 2023/03/07
CRDT- 2023/03/07 13:23
PHST- 2023/04/06 10:16 [medline]
PHST- 2023/03/08 06:00 [pubmed]
PHST- 2023/03/07 13:23 [entrez]
PHST- 2023/03/07 00:00 [pmc-release]
AID - GI-00181-2022 [pii]
AID - 10.1152/ajpgi.00181.2022 [doi]
PST - ppublish
SO  - Am J Physiol Gastrointest Liver Physiol. 2023 May 1;324(5):G389-G403. doi: 
      10.1152/ajpgi.00181.2022. Epub 2023 Mar 7.