Summary of Study ST003422

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 IDST003422
Study TitleImpact of ACLY and ACSS2 on the development of MASLD and phosphatidylcholines levels 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. Prior work has shown that phosphatidylcholines (PCs) can serve as PPARa ligands, and specifically, PC 16:0/18:1 has been established as an endogenous ligand. PC 16:0/18:1 abundance has also been found to be regulated in a circadian manner dependent on the fatty acid synthesis pathway. Since PCs as a class are suppressed in the liver ACLY KO mice, we asked if PC 16:0/18:1 is specifically reduced, finding that it its abundance is lower in the ACLY and ACLY/ACSS2 KOs.
Institute
Salk Institute for Biological Studies
Last NameKuna
First NameRamya
Address10010 N Torrey Pines Rd, La Jolla, California, 92037, USA
Emailrkuna@salk.edu
Phone8582038321
Submit Date2024-08-13
Raw Data AvailableYes
Raw Data File Type(s)d
Analysis Type DetailLC-MS
Release Date2024-09-10
Release Version1
Ramya Kuna Ramya Kuna
https://dx.doi.org/10.21228/M83N8D
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

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:SU003549
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
SA377584DF-1210_ACSS2F/F_CRECRE Mouse liver
SA377585DF-1228_ACLY_ACSS2 F/F_CRECRE Mouse liver
SA377586DF-1226_ACLY_ACSS2 F/F_CRECRE Mouse liver
SA377587DF-1221_ACLY_ACSS2 F/F_CRECRE Mouse liver
SA377588DF-1203_ACLY_ACSS2 F/F_CRECRE Mouse liver
SA377589DF-1201_ACLY_ACSS2 F/F_CRECRE Mouse liver
SA377590DF-1199_ACLY_ACSS2 F/F_CRECRE Mouse liver
SA377591DF-1231_ACSS2F/F_CRECRE Mouse liver
SA377592DF-1229_ACSS2F/F_CRECRE Mouse liver
SA377593DF-1218_ACSS2F/F_CRECRE Mouse liver
SA377594DF-1212_ACSS2F/F_CRECRE Mouse liver
SA377595DF-1205_ACSS2F/F_CRECRE Mouse liver
SA377596DF-1197_ACLY F/F_CRECRE Mouse liver
SA377597DF-1225_ACLY F/F_CRECRE Mouse liver
SA377598DF-1223_ACLY F/F_CRECRE Mouse liver
SA377599DF-1215_ACLY F/F_CRECRE Mouse liver
SA377600DF-1213_ACLY F/F_CRECRE Mouse liver
SA377601DF-1208_ACLY F/F_CRECRE Mouse liver
SA377602DF-1206_ACSS2F/F_GFPGFP Mouse liver
SA377603DF-1222_ACLY_ACSS2 F/F_GFPGFP Mouse liver
SA377604DF-1209_ACLY F/F_GFPGFP Mouse liver
SA377605DF-1214_ACLY F/F_GFPGFP Mouse liver
SA377606DF-1216_ACLY F/F_GFPGFP Mouse liver
SA377607DF-1224_ACLY F/F_GFPGFP Mouse liver
SA377608DF-1227_ACLY_ACSS2 F/F_GFPGFP Mouse liver
SA377609DF-1200_ACLY_ACSS2 F/F_GFPGFP Mouse liver
SA377610DF-1220_ACLY_ACSS2 F/F_GFPGFP Mouse liver
SA377611DF-1202_ACLY_ACSS2 F/F_GFPGFP Mouse liver
SA377612DF-1211_ACSS2F/F_GFPGFP Mouse liver
SA377613DF-1198_ACLY_ACSS2 F/F_GFPGFP Mouse liver
SA377614DF-1204_ACSS2F/F_GFPGFP Mouse liver
SA377615DF-1207_ACLY F/F_GFPGFP Mouse liver
SA377616DF-1230_ACSS2F/F_GFPGFP Mouse liver
SA377617DF-1219_ACSS2F/F_GFPGFP Mouse liver
SA377618DF-1217_ACSS2F/F_GFPGFP Mouse liver
SA377619DF-1196_ACLY F/F_GFPGFP Mouse liver
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Collection:

Collection ID:CO003542
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

Treatment:

Treatment ID:TR003558
Treatment Summary:Male mice with deletion of hepatic ACLY (ACLY KO), ACLY and ACSS2 (double KO, DKO), and respective controls (wildtype, WT) are on western diet for 22 weeks, before sacrificing liver samples were collected using Wollenberger clamps pre-cooled to the temperature of liquid nitrogen and stored at -80 C until analysis.

Sample Preparation:

Sampleprep ID:SP003556
Sampleprep Summary:Liver samples were collected using Wollenberger clamps pre-cooled to the temperature of liquid nitrogen and stored at -80 C until analysis.

Combined analysis:

Analysis ID AN005621
Analysis type MS
Chromatography type Reversed phase
Chromatography system Waters Acquity
Column Waters Acquity BEH C18 (100 x 2mm, 1.7um)
MS Type ESI
MS instrument type Triple quadrupole
MS instrument name Agilent 6460 QQQ
Ion Mode POSITIVE
Units relative abundance/mg tissue

Chromatography:

Chromatography ID:CH004271
Instrument Name:Waters Acquity
Column Name:Waters Acquity BEH C18 (100 x 2mm, 1.7um)
Column Temperature:40˚C
Flow Gradient:0 min, 82% B; 3 min, 82% B; 4 min, 90% B; 18 min, 99% B; 25 min, 99% B; 27 min, 82% B; 30 min, 82% B
Flow Rate:0.5 mL/min
Solvent A:100% water; 0.2% formic acid; 2 mM ammonium formate
Solvent B:100% methanol; 0.2% formic acid; 1 mM ammonium formate
Chromatography Type:Reversed phase

MS:

MS ID:MS005345
Analysis ID:AN005621
Instrument Name:Agilent 6460 QQQ
Instrument Type:Triple quadrupole
MS Type:ESI
MS Comments:PC 16:0/18:1 species were analyzed by multiple reaction monitoring of the transition from precursor to product ions at associated optimized collision energies, and fragmentor voltages using Agilent Masshunter. The m/z values of the
Ion Mode:POSITIVE
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