Summary of Study ST003421

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 IDST003421
Study TitleBPA regulates the abundance of endogenous PPARa ligands and fatty acid oxidation
Study SummaryGiven the regulation of PPARa(Peroxisome proliferator-activated receptor alpha)-dependent gene expression in the absence of ACLY, we postulated that endogenous PPARa ligand availability might be altered. 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 KO.
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 Date2024-08-05
Raw Data AvailableYes
Raw Data File Type(s)d
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

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:SU003548
Subject Type:Mammal
Subject Species:Mus musculus
Taxonomy ID:10090
Genotype Strain:C57BL/6J

Factors:

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

mb_sample_id local_sample_id Genotype Sample source
SA377559Alb_1985_12_KO VehicleLACLYKO Mouse liver
SA377560Alb_1994_21_KO BPALACLYKO Mouse liver
SA377561Alb_1990_17_KO BPALACLYKO Mouse liver
SA377562Alb_1989_16_KO BPALACLYKO Mouse liver
SA377563Alb_1986_13_KO BPALACLYKO Mouse liver
SA377564Alb_1984_11_KO BPALACLYKO Mouse liver
SA377565Alb_1981_8_KO BPALACLYKO Mouse liver
SA377566Alb_1977_4_KO BPALACLYKO Mouse liver
SA377567Alb_1993_20_KO VehicleLACLYKO Mouse liver
SA377568Alb_1992_19_KO VehicleLACLYKO Mouse liver
SA377569Alb_1987_14_KO VehicleLACLYKO Mouse liver
SA377570Alb_1980_7_KO VehicleLACLYKO Mouse liver
SA377571Alb_1979_6_KO VehicleLACLYKO Mouse liver
SA377572Alb_1975_2_KO VehicleLACLYKO Mouse liver
SA377573Alb_1978_5_WT VehicleWild-type Mouse liver
SA377574Alb_1997_24_WT BPAWild-type Mouse liver
SA377575Alb_1995_22_WT BPAWild-type Mouse liver
SA377576Alb_1991_18_WT BPAWild-type Mouse liver
SA377577Alb_1988_15_WT BPAWild-type Mouse liver
SA377578Alb_1982_9_WT BPAWild-type Mouse liver
SA377579Alb_1976_3_WT BPAWild-type Mouse liver
SA377580Alb_3703_25_WT VehicleWild-type Mouse liver
SA377581Alb_1996_23_WT VehicleWild-type Mouse liver
SA377582Alb_1983_10_WT VehicleWild-type Mouse liver
SA377583Alb_1974_1_WT VehicleWild-type Mouse liver
Showing results 1 to 25 of 25

Collection:

Collection ID:CO003541
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:TR003557
Treatment Summary:To test the effect of BPA on hepatic steatosis, we placed WT and LAKO mice on WD for 6 weeks, with 10 mg/kg BPA daily oral gavage over the last 3 weeks, a dose previously shown to be effective in reducing steatosis. Quantification of lipids by mass spectrometry demonstrated that ACLY deficiency increased abundance of PC 16:0/18:1.

Sample Preparation:

Sampleprep ID:SP003555
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).

Combined analysis:

Analysis ID AN005620
Analysis type MS
Chromatography type Reversed phase
Chromatography system Agilent 1290 Infinity II
Column Phenomenex Kinetex C8 (100 x 2.1mm,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:CH004270
Instrument Name:Agilent 1290 Infinity II
Column Name:Phenomenex Kinetex C8 (100 x 2.1mm,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:MS005344
Analysis ID:AN005620
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 precursor and product ions are provided in the metabolite metadata section.
Ion Mode:POSITIVE
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