Evidence map›Paper›PMID 39733992›Full record

ArticleThe American journal of pathology2025

P46Shc Inhibits Mitochondrial ACAA2 Thiolase, Exacerbating Mitochondrial Injury and Inflammation in Aging Livers.

Yuan Li, Weiguo Fan, Tzu-Han Lo, Joy X Jiang, Sarah R Fish, Alexey Tomilov, Antonios Chronopoulos, Vidushi Bansal, Gergely Mozes, Lorand Vancza and 11 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The American journal of pathology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

21 authors.

Yuan LiDivision of Gastroenterology and Hepatology, Stanford University, Stanford, California; Palo Alto VA Medical Center, Palo Alto, California.
Weiguo FanDivision of Gastroenterology and Hepatology, Stanford University, Stanford, California; Palo Alto VA Medical Center, Palo Alto, California.
Tzu-Han LoDivision of Gastroenterology and Hepatology, Stanford University, Stanford, California; Palo Alto VA Medical Center, Palo Alto, California.
Joy X JiangDivision of Gastroenterology and Hepatology, UC Davis Medical Center, Sacramento, California.
Sarah R FishDivision of Gastroenterology and Hepatology, UC Davis Medical Center, Sacramento, California.
Alexey TomilovDepartment of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, California.
Antonios ChronopoulosDivision of Gastroenterology and Hepatology, Stanford University, Stanford, California; Palo Alto VA Medical Center, Palo Alto, California.
Vidushi BansalDivision of Gastroenterology and Hepatology, Stanford University, Stanford, California; Palo Alto VA Medical Center, Palo Alto, California.
Gergely MozesDivision of Gastroenterology and Hepatology, Stanford University, Stanford, California; Palo Alto VA Medical Center, Palo Alto, California.
Lorand VanczaDivision of Gastroenterology and Hepatology, Stanford University, Stanford, California; Palo Alto VA Medical Center, Palo Alto, California.
Koshi KunimotoDivision of Gastroenterology and Hepatology, Stanford University, Stanford, California; Palo Alto VA Medical Center, Palo Alto, California.
Jiayu YeDivision of Gastroenterology and Hepatology, Stanford University, Stanford, California; Palo Alto VA Medical Center, Palo Alto, California.
Laren BeckerDivision of Gastroenterology and Hepatology, Stanford University, Stanford, California; Palo Alto VA Medical Center, Palo Alto, California.
Suvarthi DasDivision of Gastroenterology and Hepatology, Stanford University, Stanford, California; Palo Alto VA Medical Center, Palo Alto, California.
Hyesuk ParkDivision of Gastroenterology and Hepatology, Stanford University, Stanford, California; Palo Alto VA Medical Center, Palo Alto, California.
Yi WeiDivision of Gastroenterology and Hepatology, Stanford University, Stanford, California; Palo Alto VA Medical Center, Palo Alto, California.
Sara RanjbarvaziriDepartment of Pediatrics, Stanford University, Stanford, California; Cardiovascular Research Institute, Stanford University, Stanford, California.
Daniel BernsteinDepartment of Pediatrics, Stanford University, Stanford, California; Cardiovascular Research Institute, Stanford University, Stanford, California.
Jon RamseyDepartment of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, California.
Gino CortopassiDepartment of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, California.
Natalie J TörökDivision of Gastroenterology and Hepatology, Stanford University, Stanford, California; Palo Alto VA Medical Center, Palo Alto, California. Electronic address: ntorok@stanford.edu.

Funding

Matrix in pre-cirrhotic HCCR01CA277710 · NCI · STANFORD UNIVERSITY · PI Natalie J. Torok · 2023 to 2026
$2.3M
Targeting Shc to reduce inflammation and fibrosis in the aging liverR01AG060726 · NIA · PALO ALTO VETERANS INSTIT FOR RESEARCH · PI CORTOPASSI, GINO A, TOROK, NATALIE J. · 2018 to 2022
$1.9M
Common CD36-dependent gut-brain neuroimmune pathway regulates disruption of intestinal motility in Alzheimer's DiseaseR21AG077521 · NIA · STANFORD UNIVERSITY · PI BECKER, LAREN, SHAMLOO, MEHRDAD · 2022 to 2022
$437k
Fumarates for Alcoholic Liver DiseaseR21AA029558 · NIAAA · UNIVERSITY OF CALIFORNIA AT DAVIS · PI JIANG, XIAOSONG JOY · 2022 to 2023
$420k
BLRD VA I01 BX002418NCI NIH HHS R01 CA277710NIAAA NIH HHS R21 AA029558NIA NIH HHS R01 AG060726NIA NIH HHS R21 AG077521
6 · The paper itself

Abstract

Mitochondrial maladaptation and dysfunction contribute to the progression of metabolic dysfunction-associated steatohepatitis (MASH). Induction of Shc is implicated in progressive MASH during aging and the cytoplasmic p52Shc isoform in the activation of redox enzyme NOX2. The mitochondrial Shc isoform p46Shc represses acetyl-coenzyme A acyltransferase 2 (ACAA2) in vitro. ACAA2 is a key enzyme for lipid β-oxidation; however, the metabolic consequences of in vivo p46Shc induction are unknown. In the current study, p46Shc-inducible mice were generated; these and littermate controls were aged and fed chow or fast-food (high-fat and high-fructose) diet. p46Shc induction increased liver injury, inflammation, and lipid peroxidation. p46Shc overexpression did not significantly change liver triglycerides. On electron microscopy studies, mitochondria were swollen with aberrant cristae. p46Shc induction reduced mitochondrial oxygen consumption as measured by Oroboros, as well as suppressed the production of β-hydroxybutyrate, the central metabolite of therapeutic ketosis. Mitochondria exhibited increased production of reactive oxidative species. By contrast, the expression of dominant negative p46Shc reduced ACAA2 thiolase activity, improved β-oxidation, and reduced lipid peroxidation and production of reactive oxidative species. In summary, these studies support the concept that p46Shc induction in aging represses ACAA2, resulting in decreased mitochondrial β-oxidation and increased lipid peroxidation. Maintaining β-oxidation and ketogenesis could prevent liver injury, and targeting Shc-related maladaptive responses could be a successful therapeutic strategy in aging/MASH.

Indexed as

Acetyl-CoA C-AcyltransferaseAgingInflammationLiverMitochondriaMitochondria, LiverSrc Homology 2 Domain-Containing, Transforming Protein 1AnimalsLipid PeroxidationMaleMiceMice, Inbred C57BLMice, TransgenicAcetyl-CoA C-AcyltransferaseShc1 protein, mouseSrc Homology 2 Domain-Containing, Transforming Protein 1

Identifiers

PMID39733992
PMCPMC11841488

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.