PMID- 37124481
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231102
IS  - 2096-2878 (Print)
IS  - 2542-5684 (Electronic)
VI  - 6
IP  - 4
DP  - 2022 Dec
TI  - Liver-adipose tissue crosstalk in alcohol-associated liver disease: The role of 
      mTOR.
PG  - 227-237
LID - 10.1016/j.livres.2022.11.006 [doi]
AB  - BACKGROUND: Alcohol-associated liver disease (ALD) is a major chronic liver 
      disease around the world without successful treatment. Acute alcoholic hepatitis 
      is one of the most severe forms of ALD with high mortality, which is often 
      associated with binge drinking. Alcohol drinking dysregulates lipid metabolism, 
      increases adipose tissue lipolysis, and induces liver steatosis and adipose 
      tissue atrophy. Increasing evidence implicates that crosstalk of liver and 
      adipose tissue in the pathogenesis of ALD. Mechanistic target of rapamycin (mTOR) 
      is a phosphatidylinositol 3-kinase (PI3K)-like serine/threonine protein kinase 
      that regulates lipid metabolism, cell proliferation and autophagy. However, the 
      role of mTOR in regulating adipose-liver crosstalk in binge drinking-induced 
      organ damage remains unclear. METHODS: We generated liver-specific and 
      adipocyte-specific regulatory-associated protein of mTOR (Rptor) knockout (Rptor 
      (LKO) and Rptor (AKO)) as well as Mtor knockout (Mtor (LKO) and Mtor (AKO)) mice, 
      by crossing Rptor (flox) and Mtor (flox) mice with albumin Cre or adiponectin Cre 
      mice, respectively. In addition, we generated liver and adipocyte double deletion 
      of Rptor or Mtor (Mtor (LAKO) and Rptor (LAKO)) mice. The knockout mice with 
      their matched wild-type littermates (Rptor (WT) and Mtor (WT)) were subjected to 
      acute gavage of 7 g/kg ethanol. RESULTS: Mice with adipocyte deletion of Rptor or 
      Mtor developed hepatomegaly and adipose tissue atrophy. Alcohol gavage increased 
      liver injury, hepatic steatosis and inflammation in mouse livers as demonstrated 
      by elevated serum alanine aminotransferase activities, increased hepatic levels 
      of triglyceride and increased hepatic numbers of CD68 positive macrophages in 
      mouse livers after alcohol gavage. Liver injury was further exacerbated by 
      deletion of adipocyte Rptor or Mtor. Serum adipokine array analysis revealed that 
      increased levels of pro-inflammatory cytokines IL-6 and TNFalpha as well as chemokine 
      MCP-1 following acute alcohol gavage in wild-type mice, which were further 
      increased in adipocyte-specific Mtor or Rptor knockout mice. Conversely, levels 
      of anti-inflammatory cytokine IL-10 decreased in adipocyte-specific Mtor or Rptor 
      knockout mice. The levels of circulating fibroblast growth factor 21 (FGF21) 
      increased whereas levels of circulating adiponectin and fetuin A decreased in 
      wild-type mice after alcohol gavage. Intriguingly, adipocyte-specific Mtor or 
      Rptor knockout mice already had decreased basal level of FGF21 which increased by 
      alcohol gavage. Moreover, adipocyte-specific Mtor or Rptor knockout mice already 
      had increased basal level of adiponectin and decreased fetuin A which were not 
      further changed by alcohol gavage. CONCLUSIONS: Adipocyte but not hepatocyte 
      ablation of Mtor pathway contributes to acute alcohol-induced liver injury with 
      increased inflammation. Our results demonstrate the critical role of adipocyte 
      mTOR in regulating the adipose-liver crosstalk in ALD.
FAU - Rodriguez, Yssa
AU  - Rodriguez Y
AD  - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas 
      Medical Center, Kansas City, KS, USA.
FAU - Dunfield, Jack
AU  - Dunfield J
AD  - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas 
      Medical Center, Kansas City, KS, USA.
FAU - Roderique, Tyson
AU  - Roderique T
AD  - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas 
      Medical Center, Kansas City, KS, USA.
FAU - Ni, Hong-Min
AU  - Ni HM
AD  - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas 
      Medical Center, Kansas City, KS, USA.
LA  - eng
GR  - P20 GM144269/GM/NIGMS NIH HHS/United States
GR  - P30 GM118247/GM/NIGMS NIH HHS/United States
GR  - R21 AA026904/AA/NIAAA NIH HHS/United States
GR  - R56 DK129234/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20221118
PL  - China
TA  - Liver Res
JT  - Liver research
JID - 101705555
PMC - PMC10134744
MID - NIHMS1869594
OTO - NOTNLM
OT  - Adipokine
OT  - Adipose atrophy
OT  - Alcohol-associated liver disease (ALD)
OT  - Liver injury
OT  - Liver-adipose tissue crosstalk
OT  - Mechanistic target of rapamycin (mTOR)
COIS- Declaration of competing interest The authors declare that they have no conflict 
      of interest.
EDAT- 2023/05/01 06:42
MHDA- 2023/05/01 06:43
PMCR- 2023/04/27
CRDT- 2023/05/01 03:45
PHST- 2023/05/01 06:43 [medline]
PHST- 2023/05/01 06:42 [pubmed]
PHST- 2023/05/01 03:45 [entrez]
PHST- 2023/04/27 00:00 [pmc-release]
AID - 10.1016/j.livres.2022.11.006 [doi]
PST - ppublish
SO  - Liver Res. 2022 Dec;6(4):227-237. doi: 10.1016/j.livres.2022.11.006. Epub 2022 
      Nov 18.