Summary of Study ST003423

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002116. The data can be accessed directly via it's Project DOI: 10.21228/M83N8D This work is supported by NIH grant, U2C- DK119886.

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This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST003423
Study TitleImpact of ACLY and ACSS2 on the development of MASLD on longterm Western diet
Study SummaryTo further assess the impact of ACLY and ACSS2 on the development of MASLD on Western diet, we also carried out longer term experiments, in which mice remained on diet for 22 weeks. Exacerbated steatosis was apparent in the liver ACLY KO and DKO mice, both histologically and by TAG quantification. Further lipid analysis by LC-MS revealed elevated DAGs and cholesterol esters (CEs) in ACLY-deficient and DKO livers, along with reduced abundance of phosphatidylcholines (PCs). Together the data indicate that ACLY deficiency results in perturbed lipid metabolism in the liver, with accumulation of TAGs, DAGs, and CEs.
Institute
Salk Institute for Biological Studies
Last NameKUNA
First NameRAMYA
Address10010 N Torrey Pines Rd, La Jolla, California, 92037, USA
Emailrkuna@salk.edu
Phone8584534100
Submit Date2024-08-13
Raw Data AvailableYes
Raw Data File Type(s)mzXML
Analysis Type DetailLC-MS
Release Date2024-08-26
Release Version1
RAMYA KUNA RAMYA KUNA
https://dx.doi.org/10.21228/M83N8D
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR002116
Project DOI:doi: 10.21228/M83N8D
Project Title:Bempedoic acid improves diet-induced steatosis independent of hepatic ACLY
Project Type:MS quantitative analysis
Project Summary:ATP citrate lyase (ACLY) synthesizes acetyl-CoA for de novo lipogenesis (DNL), which is elevated in metabolic dysfunction-associated steatotic liver disease. Hepatic ACLY is inhibited by the LDL-cholesterol lowering drug bempedoic acid (BPA), which also improves steatosis in mice. Indeed, BPA potently suppresses hepatic DNL and increases fat catabolism. However, it is unclear if ACLY is the relevant molecular target in reducing liver triglyceride, particularly since the acetyl-CoA synthetase ACSS2 can compensate for ACLY deficiency to provision acetyl-CoA for DNL. We show that on a Western diet, loss of hepatic ACLY alone or ACLY and ACSS2 together unexpectedly exacerbates steatosis, linked to reduced hepatic abundance of endogenous PPARa (Peroxisome proliferator-activated receptor alpha) ligands and lower expression of PPARa target genes controlling fatty acid oxidation. Importantly, BPA treatment ameliorates Western diet-mediated triglyceride accumulation in both WT and liver ACLY knockout mice, indicating that its primary effects on hepatic lipid metabolism are independent of ACLY. Together, these data indicate that hepatic ACLY plays an unexpected role in restraining diet-dependent lipid accumulation, and that BPA improves steatosis independent of ACLY.
Institute:Salk Institute for Biological Studies
Department:Molecular and Cell Biology Laboratory
Laboratory:Metallo Lab
Last Name:Kuna
First Name:Ramya
Address:10010 N Torrey Pines Rd, La Jolla, California, 92037, USA
Email:rkuna@salk.edu
Phone:8582038321

Subject:

Subject ID:SU003550
Subject Type:Mammal
Subject Species:Mus musculus
Taxonomy ID:10090

Factors:

Subject type: Mammal; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Genotype Sample source
SA377620DF-1210_ACSS2F/F_CRECRE Mouse liver
SA377621DF-1228_ACLY_ACSS2 F/F_CRECRE Mouse liver
SA377622DF-1226_ACLY_ACSS2 F/F_CRECRE Mouse liver
SA377623DF-1221_ACLY_ACSS2 F/F_CRECRE Mouse liver
SA377624DF-1203_ACLY_ACSS2 F/F_CRECRE Mouse liver
SA377625DF-1201_ACLY_ACSS2 F/F_CRECRE Mouse liver
SA377626DF-1199_ACLY_ACSS2 F/F_CRECRE Mouse liver
SA377627DF-1231_ACSS2F/F_CRECRE Mouse liver
SA377628DF-1229_ACSS2F/F_CRECRE Mouse liver
SA377629DF-1218_ACSS2F/F_CRECRE Mouse liver
SA377630DF-1212_ACSS2F/F_CRECRE Mouse liver
SA377631DF-1205_ACSS2F/F_CRECRE Mouse liver
SA377632DF-1197_ACLY F/F_CRECRE Mouse liver
SA377633DF-1225_ACLY F/F_CRECRE Mouse liver
SA377634DF-1223_ACLY F/F_CRECRE Mouse liver
SA377635DF-1215_ACLY F/F_CRECRE Mouse liver
SA377636DF-1213_ACLY F/F_CRECRE Mouse liver
SA377637DF-1208_ACLY F/F_CRECRE Mouse liver
SA377638DF-1206_ACSS2F/F_GFPGFP Mouse liver
SA377639DF-1222_ACLY_ACSS2 F/F_GFPGFP Mouse liver
SA377640DF-1209_ACLY F/F_GFPGFP Mouse liver
SA377641DF-1214_ACLY F/F_GFPGFP Mouse liver
SA377642DF-1216_ACLY F/F_GFPGFP Mouse liver
SA377643DF-1224_ACLY F/F_GFPGFP Mouse liver
SA377644DF-1227_ACLY_ACSS2 F/F_GFPGFP Mouse liver
SA377645DF-1200_ACLY_ACSS2 F/F_GFPGFP Mouse liver
SA377646DF-1220_ACLY_ACSS2 F/F_GFPGFP Mouse liver
SA377647DF-1202_ACLY_ACSS2 F/F_GFPGFP Mouse liver
SA377648DF-1211_ACSS2F/F_GFPGFP Mouse liver
SA377649DF-1198_ACLY_ACSS2 F/F_GFPGFP Mouse liver
SA377650DF-1204_ACSS2F/F_GFPGFP Mouse liver
SA377651DF-1207_ACLY F/F_GFPGFP Mouse liver
SA377652DF-1230_ACSS2F/F_GFPGFP Mouse liver
SA377653DF-1219_ACSS2F/F_GFPGFP Mouse liver
SA377654DF-1217_ACSS2F/F_GFPGFP Mouse liver
SA377655DF-1196_ACLY F/F_GFPGFP Mouse liver
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Collection:

Collection ID:CO003543
Collection Summary:Liver samples were collected using Wollenberger clamps pre-cooled to the temperature of liquid nitrogen and stored at -80 C until analysis.
Sample Type:Liver
Storage Conditions:-80℃

Treatment:

Treatment ID:TR003559
Treatment Summary:BPA(Bempedoic acid) was first prepared as a disodium salt aqueous solution by making a 2:1 molar ratio of NaOH to BPA in water. While stirring, carboxymethylcellulose (Sigma-Aldrich C5678) was added at a final concentration of 0.5% w/v. Tween-20 was added at a final concentration of 0.025%. pH was measured and adjusted with HCl to pH 7. Vehicle solution was prepared with the same method, excluding BPA. BPA or vehicle was administered to mice daily in the morning by oral gavage at either 10 or 30 mg/kg body weight or equivalent vehicle volume for indicated lengths of time. The last dose of BPA was administered 2-4 hours prior to tissue collection.
Treatment Compound:BPA

Sample Preparation:

Sampleprep ID:SP003557
Sampleprep Summary:Samples were extracted with 400 ul of methanol (-20 C), 100 ul of water (ice-cold), 400 saline (ice-cold), and 1000 ul of chloroform (-20 C).
Processing Storage Conditions:Room temperature
Extract Storage:4℃

Combined analysis:

Analysis ID AN005622
Analysis type MS
Chromatography type Reversed phase
Chromatography system Thermo Vanquish
Column Thermo Accucore C30 (150 x 2.1mm,2.6um)
MS Type ESI
MS instrument type Ion trap
MS instrument name Thermo Q Exactive Orbitrap
Ion Mode POSITIVE
Units relative abundance/mg tissue

Chromatography:

Chromatography ID:CH004272
Chromatography Summary:30% to 43% B from 3-8 min, then from 43% to 50% B from 8-9 min, then 50-90% B from 9-18 min, then 90-99% B from 18-26 min, then held at 99% B from 26-30 min, before returning to 30% B in 6 min and held for a further 4 min
Instrument Name:Thermo Vanquish
Column Name:Thermo Accucore C30 (150 x 2.1mm,2.6um)
Column Temperature:40
Flow Gradient:0 min, 30% B; 3 min, 30% B; 8 min, 43% B; 9 min, 50% B; 18 min, 90% B; 26 min, 99% B; 30 min, 99%B; 36 min, 30% B
Flow Rate:0.2 mL/min
Solvent A:40% water/60% acetonitrile; 0.1% formic acid; 10 mM ammonium formate
Solvent B:90% isopropanol/10% acetonitrile; 0.1% formic acid; 10 mM ammonium formate
Chromatography Type:Reversed phase

MS:

MS ID:MS005346
Analysis ID:AN005622
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Ion trap
MS Type:ESI
MS Comments:El-MAVEN
Ion Mode:POSITIVE
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