PMID- 37273159
OWN - NLM
STAT- MEDLINE
DCOM- 20231115
LR  - 20231122
IS  - 2509-2723 (Electronic)
IS  - 2509-2715 (Print)
IS  - 2509-2723 (Linking)
VI  - 45
IP  - 5
DP  - 2023 Oct
TI  - Coordinated transcriptional upregulation of oxidative metabolism proteins in 
      long-lived endocrine mutant mice.
PG  - 2967-2981
LID - 10.1007/s11357-023-00849-8 [doi]
AB  - Caloric restriction (CR), which extends lifespan in rodents, leads to increased 
      hepatic fatty acid beta-oxidation and oxidative phosphorylation (OXPHOS), with 
      parallel changes in proteins and their mRNAs. Genetic mutants that extend 
      lifespan, including growth hormone receptor knockout (GHRKO) and Snell dwarf (SD) 
      mice, have lower respiratory quotient, suggesting increased reliance on fatty 
      acid oxidation, but the molecular mechanism(s) of this metabolic shift have not 
      yet been worked out. Here we show that both GHRKO and SD mice have significantly 
      higher mRNA and protein levels of enzymes involved in mitochondrial and 
      peroxisomal fatty acid beta-oxidation. In addition, multiple subunits of OXPHOS 
      complexes I-IV are upregulated in GHRKO and SD livers, and Complex V subunit 
      ATP5a is upregulated in liver of GHRKO mice. Expression of these genes is 
      regulated by a group of nuclear receptors and transcription factors including 
      peroxisome proliferator-activated receptors (PPARs) and estrogen-related 
      receptors (ERRs). We found that levels of these nuclear receptors and their 
      co-activator PGC-1alpha were unchanged or downregulated in liver of GHRKO and SD 
      mice. In contrast, NCOR1, a co-repressor for the same receptors, was 
      significantly downregulated in the two long-lived mouse models, suggesting a 
      plausible mechanism for the changes in FAO and OXPHOS proteins. Hepatic levels of 
      HDAC3, a co-factor for NCOR1 transcriptional repression, were also downregulated. 
      The role of NCOR1 is well established in the contexts of cancer and metabolic 
      disease, but may provide new mechanistic insights into metabolic control in 
      long-lived mouse models.
CI  - (c) 2023. The Author(s), under exclusive licence to American Aging Association.
FAU - Elmansi, Ahmed M
AU  - Elmansi AM
AD  - Department of Pathology, University of Michigan School of Medicine, Ann Arbor, 
      MI, USA.
FAU - Miller, Richard A
AU  - Miller RA
AUID- ORCID: 0000-0001-9266-9649
AD  - Department of Pathology, University of Michigan School of Medicine, Ann Arbor, 
      MI, USA. millerr@umich.edu.
AD  - University of Michigan Geriatrics Center, Ann Arbor, MI, USA. millerr@umich.edu.
LA  - eng
GR  - T32 AG000114/AG/NIA NIH HHS/United States
GR  - U19 AG023122/AG/NIA NIH HHS/United States
GR  - P30 AG024824/AG/NIA NIH HHS/United States
GR  - UH3 AG064706/AG/NIA NIH HHS/United States
GR  - UH2 AG064706/AG/NIA NIH HHS/United States
GR  - AG000114/AG/NIA NIH HHS/United States
GR  - Z01 AG000114/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20230605
PL  - Switzerland
TA  - Geroscience
JT  - GeroScience
JID - 101686284
RN  - 0 (Receptors, Somatotropin)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Fatty Acids)
SB  - IM
MH  - Mice
MH  - Animals
MH  - Up-Regulation
MH  - *Receptors, Somatotropin/genetics/metabolism
MH  - Mice, Knockout
MH  - *Receptors, Cytoplasmic and Nuclear/genetics/metabolism
MH  - Oxidative Phosphorylation
MH  - Fatty Acids
MH  - Oxidative Stress
PMC - PMC10643730
OTO - NOTNLM
OT  - GHRKO
OT  - Longevity
OT  - Mitochondria
OT  - NCOR1
OT  - OXPHOS
OT  - beta-oxidation
COIS- The authors have no relevant financial or non-financial interests to disclose.
EDAT- 2023/06/05 13:04
MHDA- 2023/11/15 06:42
PMCR- 2023/06/05
CRDT- 2023/06/05 11:13
PHST- 2023/04/10 00:00 [received]
PHST- 2023/05/31 00:00 [accepted]
PHST- 2023/11/15 06:42 [medline]
PHST- 2023/06/05 13:04 [pubmed]
PHST- 2023/06/05 11:13 [entrez]
PHST- 2023/06/05 00:00 [pmc-release]
AID - 10.1007/s11357-023-00849-8 [pii]
AID - 849 [pii]
AID - 10.1007/s11357-023-00849-8 [doi]
PST - ppublish
SO  - Geroscience. 2023 Oct;45(5):2967-2981. doi: 10.1007/s11357-023-00849-8. Epub 2023 
      Jun 5.