Last update 01 Nov 2024

ACAT1

Last update 01 Nov 2024

Basic Info

Synonyms

ACAT, ACAT1, acetoacetyl Coenzyme A thiolase

+ [7]

Introduction

This is one of the enzymes that catalyzes the last step of the mitochondrial beta-oxidation pathway, an aerobic process breaking down fatty acids into acetyl-CoA (PubMed:1715688, PubMed:7728148, PubMed:9744475). Using free coenzyme A/CoA, catalyzes the thiolytic cleavage of medium- to long-chain 3-oxoacyl-CoAs into acetyl-CoA and a fatty acyl-CoA shortened by two carbon atoms (PubMed:1715688, PubMed:7728148, PubMed:9744475). The activity of the enzyme is reversible and it can also catalyze the condensation of two acetyl-CoA molecules into acetoacetyl-CoA (PubMed:17371050). Thereby, it plays a major role in ketone body metabolism (PubMed:17371050, PubMed:1715688, PubMed:7728148, PubMed:9744475).

Drugs associated with ACAT1

E-5324

Target

ACAT1

Mechanism

ACAT1 inhibitors

Active Org.

Eisai Co., Ltd.

Originator Org.

Eisai Co., Ltd.

Active Indication

Atherosclerosis

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

R-755

Target

ACAT1

Mechanism

ACAT1 inhibitors

Active Org.

Nihon Nohyaku Co., Ltd.

Originator Org.

Nihon Nohyaku Co., Ltd.

Active Indication

Atherosclerosis

Inactive Indication

Hyperlipidemias

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

SMP-500

Target

ACAT1

Mechanism

ACAT1 inhibitors

Active Org.

Sumitomo Pharma Co., Ltd.

Originator Org.

Sumitomo Pharma Co., Ltd.

Active Indication

Atherosclerosis [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with ACAT1

NCT00078026 / TerminatedPhase 1/2

A Phase I/II Randomized Study of the Short-Term Effects of APOMINE vs Placebo in Postmenopausal Women With Osteoporosis or Low Bone Mass

Osteoporosis affects millions of postmenopausal women in the USA. The current approved treatments are all drugs that prevent bone loss and possibly result in small gains in bone mass. Another possible treatment consists of drugs that increase bone formation. There are currently two drugs that stimulate bone formation, sodium fluoride and human parathyroid hormone (hPTH). Neither of these two drugs has been approved by the FDA. APOMINE has shown significant bone formation in animal studies. In this study we plan to test whether APOMINE is able to stimulate new bone formation in women with osteoporosis or low bone mass.

Start Date01 Aug 2003

Sponsor / Collaborator

Genzyme Corp.

NCT00004049 / CompletedPhase 1

A Phase I and Pharmacokinetic Study of SR-45023A Administered Once Every 7 Days

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.
PURPOSE: Phase I trial to study the effectiveness of SR-45023A in treating patients who have locally advanced or metastatic solid tumors that have not responded to previous treatment.

Start Date01 Apr 1999

Sponsor / Collaborator

Genzyme Corp.

NCT00003822 / CompletedPhase 1

A Phase I and Pharmacokinetic Study of SR-45023A During a 14-Day Treatment Schedule

Start Date01 Aug 1998

Sponsor / Collaborator

Genzyme Corp.

100 Clinical Results associated with ACAT1

100 Translational Medicine associated with ACAT1

0 Patents (Medical) associated with ACAT1

1,525

Literatures (Medical) associated with ACAT1

01 Dec 2024·Gene

Identification of key mitochondria-related genes and their potential crosstalk role with immune pattern in Idiopathic pulmonary fibrosis

Article

Author: Zeng, Youjie ; Guo, Ren ; Ding, Zhigang ; Huang, Jun ; Xu, Huilin ; Zhang, Siyi ; Wang, Xia

BACKGROUNDIdiopathic pulmonary fibrosis (IPF) stands out as a life-threatening and one of the most severe interstitial lung diseases. The pathogenesis of IPF is not fully understood, while recent studies have highlighted the association of mitochondrial dysfunction with IPF. This study is dedicated to pinpointing crucial genes related to mitochondria that potentially impact the advancement of IPF, thereby offering new perspectives on the pathogenesis of this condition.METHODSThe Gene Expression Omnibus (GEO) database was utilized to download three datasets (GSE32537, GSE92592, and GSE150910), following which a comprehensive analysis was conducted to identify differentially expressed mitochondria-related genes (DEMTRGs) in the IPF lung tissues. Subsequently, GO and KEGG enrichment analysis of the DEMTRGs was performed. Next, external datasets and in vivo experiments were performed to validate their expression. Additionally, a Logistic regression model based on key DEMTRGs was constructed, and the model's ability to distinguish between IPF and controls was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC). Finally, gene set enrichment analysis (GSEA) and CIBERSORT algorithm were conducted.RESULTSWe identified five key DEMTRGs (ALDH18A1, ALDH1B1, MCCC1, ACAT1, and PDHA1), ALDH18A1 and ALDH1B1 exhibited upregulated expression levels, whereas MCCC1, ACAT1, and PDHA1 showed downregulation in the lung tissue of individuals with IPF. The expression levels of these key DEMTRGs were validated by an independent external dataset (GSE53845) and the bleomycin-induced pulmonary fibrosis mice. In addition, the ROCs indicated that the diagnostic model constructed based on key DEMTRGs could effectively distinguish between IPF and controls (AUC>0.8). GSEA analysis and immune-related analysis shed light on the potential mechanisms through which these key DEMTRGs influence IPF.CONCLUSIONOur research has pinpointed key genes associated with mitochondria that may ultimately contribute to the progression of IPF by exerting regulatory effects on mitochondrial function, thereby influencing multiple cellular processes.

01 Dec 2024·Phytomedicine

Qiwei Jinggan Ling regulates oxidative stress and lipid metabolism in alcoholic liver disease by activating AMPK

Article

Author: Xu, Baoling ; Cao, Houkang ; Wei, Riming ; Liu, Haiping ; Li, Bo ; Zhi, Yueping ; Wan, Weimin ; Gao, Ya ; Wu, Jianzhao ; Zhang, Kefeng ; Guo, Fengyue

BACKGROUNDAlcoholic liver disease (ALD) is a severe public health concern worldwide and there is still a lack of effective treatments. Qiwei Jinggan Ling (QJL) has protective effects against various liver injuries, but its pharmacological action on ALD has received little attention.PURPOSETo investigate the effect and mechanism of QJL on ALD in vivo and in vitro.METHODSIn vivo, an ALD mouse model was established by alcohol combined with a high-fat diet (HFD) and treated with QJL. Biochemical indicators, HE staining, and Oil Red O staining were employed to assess hepatic oxidative stress, steatosis, and alcohol metabolism. RNA sequencing analysis was performed, and the results were verified by qRT-PCR and Western blot to elucidate the hepatoprotective mechanism of QJL. In vitro, HepG2 cells were co-stimulated with NaOA (sodium oleate) and EtOH (ethanol), followed by intervention with Compound C (CC, AMPK inhibitor) and QJL-containing serum. Oil Red O, BODIPY (boron-dipyrromethene), and ROS (reactive oxygen species) staining were applied to validate the efficacy and mechanism of QJL-containing serum. The expression of AMP-activated protein kinase (AMPK) pathway-related factors was analyzed through qRT-PCR and Western blot for additional corroboration. Moreover, the key pharmacodynamic components of QJL were identified by UPLC-MS/MS and molecular docking.RESULTSIn vivo, QJL ameliorated liver structural disorders, steatosis, oxidative stress, and impaired alcohol metabolism, as indicated by biochemical indicators and histopathological assays. RNA sequencing analysis revealed that QJL reversed the expression of genes related to alcohol metabolism, fatty acid metabolism, and cholesterol metabolism. The results of qRT-PCR and Western blot were in line with those of RNA sequencing. Furthermore, it was discovered that QJL significantly upregulated the expression of p-AMPK and downregulated the expression of sterol regulatory element binding transcription factor 1 (SREBP-1c). In vitro, biochemical indicators and staining assays demonstrated that QJL-containing serum inhibited lipid accumulation and oxidative stress. The qRT-PCR and Western blot analysis revealed that QJL-containing serum markedly enhanced the expression of p-AMPK and carnitine palmitoyltransferase 1a (Cpt1a), while suppressing the expression of SREBP-1c, fatty acid synthase (Fasn), and acetyl-coenzyme A carboxylase 1 (ACC-1). However, CC inhibited the above pharmacological activities of QJL-containing serum. Additionally, (2S)-Liquiritigenin, Glycyrrhetinate, Isovitexin, Taxifolin, and Yohimbine were proved to be the key active components of QJL.CONCLUSIONQJL had the potential to be a therapeutic drug for ALD by activating the AMPK pathway, thereby regulating lipid metabolism and inhibiting oxidative stress.

25 Oct 2024·Science Advances

Mitochondrial fatty acid oxidation drives senescence

Article

Author: Odawara, Takeru ; Sugiura, Yuki ; Yamaguchi, Junji ; Ichijo, Hidenori ; Naguro, Isao ; Fujisawa, Takao ; Takahashi, Akiko ; Fukaya, Shunsuke ; Yamauchi, Shota ; Takenaka, Satoshi ; Zhou, Xiangyu ; Uchiyama, Yasuo

Cellular senescence is a stress-induced irreversible cell cycle arrest involved in tumor suppression and aging. Many stresses, such as telomere shortening and oncogene activation, induce senescence by damaging nuclear DNA. However, the mechanisms linking DNA damage to senescence remain unclear. Here, we show that DNA damage response (DDR) signaling to mitochondria triggers senescence. A genome-wide small interfering RNA screen implicated the outer mitochondrial transmembrane protein BNIP3 in senescence induction. We found that BNIP3 is phosphorylated by the DDR kinase ataxia telangiectasia mutated (ATM) and contributes to an increase in the number of mitochondrial cristae. Stable isotope labeling metabolomics indicated that the increase in cristae enhances fatty acid oxidation (FAO) to acetyl–coenzyme A (acetyl-CoA). This promotes histone acetylation and expression of the cyclin-dependent kinase inhibitor p16 INK4a . Notably, pharmacological activation of FAO alone induced senescence both in vitro and in vivo. Thus, mitochondrial energy metabolism plays a critical role in senescence induction and is a potential intervention target to control senescence.

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