Evidence map›Paper›PMID 39489289›Full record

ArticleMolecular metabolism2024

TOMM40 regulates hepatocellular and plasma lipid metabolism via an LXR-dependent pathway.

Neil V Yang, Justin Y Chao, Kelly A Garton, Tommy Tran, Sarah M King, Joseph Orr, Jacob H Oei, Alexandra Crawford, Misun Kang, Reena Zalpuri and 5 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular metabolism, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing 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

8 citing papers in PubMed.

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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

15 authors.

Neil V YangDepartment of Nutritional Sciences & Toxicology, University of California, Berkeley, CA, USA; Department of Pediatrics, University of California, San Francisco, CA, USA.
Justin Y ChaoDepartment of Pediatrics, University of California, San Francisco, CA, USA.
Kelly A GartonDepartment of Nutritional Sciences & Toxicology, University of California, Berkeley, CA, USA.
Tommy TranDepartment of Pediatrics, University of California, San Francisco, CA, USA.
Sarah M KingDepartment of Pediatrics, University of California, San Francisco, CA, USA.
Joseph OrrDepartment of Pediatrics, University of California, San Francisco, CA, USA.
Jacob H OeiDepartment of Pediatrics, University of California, San Francisco, CA, USA.
Alexandra CrawfordDepartment of Pediatrics, University of California, San Francisco, CA, USA.
Misun KangElectron Microscope Laboratory, University of California, Berkeley, CA, USA.
Reena ZalpuriElectron Microscope Laboratory, University of California, Berkeley, CA, USA.
Danielle M JorgensElectron Microscope Laboratory, University of California, Berkeley, CA, USA.
Pranav KonchadiDepartment of Medicine, University of California, San Francisco, CA, USA.
John S ChorbaDepartment of Medicine, University of California, San Francisco, CA, USA; Division of Cardiology, Zuckerberg San Francisco General Hospital, San Francisco, CA, USA.
Elizabeth TheuschDepartment of Pediatrics, University of California, San Francisco, CA, USA.
Ronald M KraussDepartment of Nutritional Sciences & Toxicology, University of California, Berkeley, CA, USA; Department of Pediatrics, University of California, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, CA, USA. Electronic address: ronald.krauss@ucsf.edu.

Funding

ICP-QQQS10OD030258 · OD · UNIVERSITY OF CALIFORNIA BERKELEY · PI JORGENS, DANIELLE MARY · 2021 to 2021
$1.6M
NIH HHS S10 OD030258
6 · The paper itself

Abstract

objectiveThe gene encoding TOMM40 (Transporter of Outer Mitochondrial Membrane 40) is adjacent to that encoding APOE, which has a central role in lipid and lipoprotein metabolism. While human genetic variants near APOE and TOMM40 have been shown to be strongly associated with plasma lipid levels, a specific role for TOMM40 in lipid metabolism has not been established, and the present study was aimed at assessing this possibility.

methodsTOMM40 was knocked down by siRNA in human hepatoma HepG2 cells, and effects on mitochondrial function, lipid phenotypes, and crosstalk between mitochondria, ER, and lipid droplets were examined. Additionally, hepatic and plasma lipid levels were measured in mice following shRNA-induced knockdown of Tomm40 shRNA.

resultsIn HepG2 cells, TOMM40 knockdown upregulated expression of APOE and LDLR in part via activation of LXRB (NR1H2) by oxysterols, with consequent increased uptake of VLDL and LDL. This is in part due to disruption of mitochondria-endoplasmic reticulum contact sites, with resulting accrual of reactive oxygen species and non-enzymatically derived oxysterols. With TOMM40 knockdown, cellular triglyceride and lipid droplet content were increased, effects attributable in part to receptor-mediated VLDL uptake, since lipid staining was significantly reduced by concomitant suppression of either LDLR or APOE. In contrast, cellular cholesterol content was reduced due to LXRB-mediated upregulation of the ABCA1 transporter as well as increased production and secretion of oxysterol-derived cholic acid. Consistent with the findings in hepatoma cells, in vivo knockdown of TOMM40 in mice resulted in significant reductions of plasma triglyceride and cholesterol concentrations, reduced hepatic cholesterol and increased triglyceride content, and accumulation of lipid droplets leading to development of steatosis.

conclusionsThese findings demonstrate a role for TOMM40 in regulating hepatic lipid and plasma lipoprotein levels and identify mechanisms linking mitochondrial function with lipid metabolism.

Indexed as

Lipid MetabolismLiver X ReceptorsMembrane Transport ProteinsMitochondrial Precursor Protein Import Complex ProteinsAnimalsApolipoproteins EHepatocytesHep G2 CellsHumansLiverMaleMiceMice, Inbred C57BLMitochondriaReceptors, LDLTriglyceridesApoE protein, humanApolipoproteins ELiver X ReceptorsMembrane Transport ProteinsMitochondrial Precursor Protein Import Complex ProteinsReceptors, LDLTOMM40 protein, humanTriglyceridesApoELipid metabolismLXRMitochondriaMitochondria-ER contact sitesTOMM40

Identifiers

PMID39489289
PMCPMC11600064

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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.