Acyl-coenzyme A: cholesterol acyltransferase family

The enzymes of the acyl-coenzyme A:cholesterol acyltransferase(ACAT)family are responsible for the in vivo synthesis of neutral lipids.They are potential drug targets for the intervention of atherosclerosis,hyperlipidemia,obesity,type II diabetes and even Alzheimer’s disease.ACAT family enzymes are integral endoplasmic reticulum(ER)membrane proteins and can be divided into ACAT branch and acyl-coenzyme A:diacylglycerol acyltransferase 1(DGAT1)branch according to their substrate specificity.The ACAT branch catalyzes synthesis of cholesteryl esters using long-chain fatty acyl-coenzyme A and cholesterol as substrates,while the DGAT1 branch catalyzes synthesis of triacylglycerols using fatty acylcoenzyme A and diacylglycerol as substrates.In this review,we mainly focus on the recent progress in the structural research of ACAT family enzymes,including their disulfide linkage,membrane topology,subunit interaction and catalysis mechanism.

Conjugated Linoleic Acid and Dietary Fats Differentially Affect Hepatic ACAT Activity and LDL-Cholesterol in Postweanling Pigs Fed Low-Fat Diets

ABSTRACT：Two separate studies tested the hypoth- esis that plasma low-density lipoprotein cholesterol LDL-C ） can be decreased by conjugated linoleic acid （CLA） by depressing hepatic acyl-coenzyme A： cholesterol acyltransferase （ACAT） activity. In the first experiment, 3 groups of 6 early-weaned piglets were fed low-fat diets containing either 1.5% CLA, 1.5% corn oil or 1.5% beef tallow;fat provided 8% of the energy intake. In the second experiment, 4 groups of 6 early-weaned piglets were fed high-fat di- ets containing either 15% beef tallow, 12% beef tal- low plus 3% CLA, 15% corn oil, or 12% corn oil plus 3% CLA; fat provided 29% of energy intake. Cholesterol was balanced across diets in both experi-ments. In pigs fed the low-fat diets, all dietary fats in- creased LDL-C and triacylglycerols and decreased high-density lipoprotein cholesterol （ HDL-C ） and very low-density lipoprotein cholesterol （VLDL-C）. LDL-C was the same in pigs fed low-fat tallow or low-fat CLA diets. However, ACAT activity was near- ly 80% higher in pigs fed the low-fat tallow diet than in pigs fed the low-fat CLA diets. All high-fat diets increased LDL-C, HDL-C and triacylglycerols equally with no effect on VLDL-C. There were no unique fat- ty acid effects of the high-fat diets on ACAT activity. We conclude that supplemental fats had differential effects on hepatic ACAT activity and LDL-C, but on- ly in pigs fed low-fat diets.

Transfer RNA-derived fragment tRF-23-Q99P9P9NDD promotes progression of gastric cancer by targeting ACADSB

Gastric cancer(GC)is one of the most common gastrointestinal tumors.As a newly discovered type of non-coding RNAs,transfer RNA(tRNA)-derived small RNAs(tsRNAs)play a dual biological role in cancer.Our previous studies have demonstrated the potential of tRF-23-Q99P9P9NDD as a diagnostic and prognostic biomarker for GC.In this work,we confirmed for the first time that tRF-23-Q99P9P9NDD can promote the proliferation,migration,and invasion of GC cells in vitro.The dual luciferase reporter gene assay confirmed that tRF-23-Q99P9P9NDD could bind to the 3'untranslated region(UTR)site of acyl-coenzyme A dehydrogenase short/branched chain(ACADSB).In addition,ACADSB could rescue the effect of tRF-23-Q99P9P9NDD on GC cells.Next,we used Gene Ontology(GO),the Kyoto Encyclopedia of Genes and Genomes(KEGG),and Gene Set Enrichment Analysis(GSEA)to find that downregulated ACADSB in GC may promote lipid accumulation by inhibiting fatty acid catabolism and ferroptosis.Finally,we verified the correlation between ACADSB and 12 ferroptosis genes at the transcriptional level,as well as the changes in reactive oxygen species(ROS)levels by flow cytometry.In summary,this study proposes that tRF-23-Q99P9P9NDD may affect GC lipid metabolism and ferroptosis by targeting ACADSB,thereby promoting GC progression.It provides a theoretical basis for the diagnostic and prognostic monitoring value of GC and opens upnew possibilities for treatment.

Acyl-CoA synthase ACSL4:an essential target in ferroptosis and fatty acid metabolism

Long-chain acyl-coenzyme A(CoA)synthase 4(ACSL4)is an enzyme that esterifies CoA into specific polyunsaturated fatty acids,such as arachidonic acid and adrenic acid.Based on accumulated evidence,the ACSL4-catalyzed biosynthesis of arachidonoyl-CoA contributes to the execution of ferroptosis by triggering phospholipid peroxidation.Ferroptosis is a type of programmed cell death caused by iron-dependent peroxidation of lipids;ACSL4 and glutathione peroxidase 4 positively and negatively regulate ferroptosis,respectively.In addition,ACSL4 is an essential regulator of fatty acid(FA)metabolism.ACSL4 remodels the phospholipid composition of cell membranes,regulates steroidogenesis,and balances eicosanoid biosynthesis.In addition,ACSL4-mediated metabolic reprogramming and antitumor immunity have attracted much attention in cancer biology.Because it facilitates the cross-talk between ferroptosis and FA metabolism,ACSL4 is also a research hotspot in metabolic diseases and ischemia/reperfusion injuries.In this review,we focus on the structure,biological function,and unique role of ASCL4 in various human diseases.Finally,we propose that ACSL4 might be a potential therapeutic target.

Skeletal Muscle Magnetic Resonance Imaging of the Lower Limbs in Late-onset Lipid Storage Myopathy with Electron Transfer Flavoprotein Dehydrogenase Gene Mutations

Background： Lipid storage myopathy （LSM） is a genetically heterogeneous group with variable clinical phenotypes. Late-onset multiple acyl-coenzyme A dehydrogenation deficiency （MADD） is a rather common form of LSM in China. Diagnosis and clinical management of it remain challenging, especially without robust muscle biopsy result and genetic detection. As the noninvasion and convenience, muscle magnetic resonance imaging （MRI） is a helpful assistant, diagnostic tool for neuromuscular disorders. However, the disease-specific MRI patterns of muscle involved and its diagnostic value in late-onset MADD have not been systematic analyzed. Methods： We assessed the MRI pattern and fat infiltration degree of the lower limb muscles in 28 late-onset MADD patients, combined with detailed clinical features and gene spectrum. Fat infiltration degree of the thigh muscle was scored while that ofgluteus was described as obvious or not. Associated muscular atrophy was defined as obvious muscle bulk reduction. Results： The mean scores were significantly different among the anterior, medial, and posterior thigh muscle groups. The mean of fat infiltration scores on posterior thigh muscle group was significantly higher than either anterior or medial thigh muscle group （P 〈 0.00 l）. Moreover, the mean score on medial thigh muscle group was significantly higher than that of anterior thigh muscle group （P 〈 0.01）. About half of the patients displayed fat infiltration and atrophy in gluteus muscles. Of 28 patients, 12 exhibited atrophy in medial and/ or posterior thigh muscle groups, especially in posterior thigh muscle group. Muscle edema pattern was not found in all the patients. Conclusions： Late-onset MADD patients show a typical muscular imaging pattern of fat infiltration and atrophy on anterior, posterior, and medial thigh muscle groups, with major involvement of posterior thigh muscle group and gluteus muscles and a sparing involvement of anterior thigh compartment. Our findings also suggest that muscle MRI of lower limbs is a helpful tool in guiding clinical evaluation on late-onset MADD.