Disease relevance of ACAT1

• A patient with severe neurologic symptoms and acetoacetyl-CoA thiolase deficiency [1].
• Genetics and molecular biology: macrophage ACAT depletion - mechanisms of atherogenesis [2].
• Nucleotide sequences of the bacteriophage T2 and T6 gene 32 mRNAs [3].

Psychiatry related information on ACAT1

• Finally, ACAT inhibitors have recently been proposed for the treatment of Alzheimer's disease[4].This study did not demonstrate a family aggregation of affective disorders in patients with T2DM [5].

High impact information on ACAT1

• In addition, nuclear molecules contain T2 RNA ase-resistant, methyl-labeled oligonucleotides ("di-" and "tri-" nucleotides) which are not found in mRNA [6].
• The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer's disease [7].
• GK07 is a compound heterozygote; the maternal allele has a novel G to T transversion at position 1136 causing Gly379 to Val substitution (G379V) of the T2 precursor [8].
• 3-Ketothiolase deficiency (3KTD) stems from a deficiency of mitochondrial acetoacetyl-coenzyme A thiolase (T2) [9].

Chemical compound and disease context of ACAT1

• The grapefruit flavonoid, naringenin, is hypocholesterolemic in vivo, and inhibits basal apolipoprotein B (apoB) secretion and the expression and activities of both ACAT and microsomal triglyceride transfer protein (MTP) in human hepatoma cells (HepG2) [10].
• In conclusion, the results suggest that F 12511, a powerful and systemic ACAT inhibitor, constitutes an appropriate tool to determine whether the inhibition of ACAT constitutes an effective therapy for the treatment of hypercholesterolemia and of atherosclerosis in man [11].
• However, a recent double-blind, placebo-controlled, randomized trial of a potent ACAT inhibitor, avasimibe, failed to show significant beneficial effects on coronary atherosclerosis assessed by intravascular ultrasound [12].

Biological context of ACAT1

• There are two adjacent in-frame AUG codons, AUG(1397-1399) and AUG(1415-1417), at 5'-terminus of the open reading frame (ORF, nt 1397-3049) of human ACAT1 mRNA corresponding to cDNA K1 [13].
• Much has been learned from mice with gene deletions for either ACAT1 or ACAT2 [14].
• Mass-production of human ACAT-1 and ACAT-2 to screen isoform-specific inhibitor: a different substrate specificity and inhibitory regulation [15].
• To develop more potent hACAT inhibitor, shikonin derivatives (5-11) were synthesized by semi-synthesis of shikonin (4), which was prepared by hydrolysis of 1-3 [16].

Anatomical context of ACAT1

• Studies in non-human primates have shown the presence of ACAT1 primarily in the Kupffer cells of the liver, in non-mucosal cell types in the intestine, and in kidney and adrenal cortical cells, whereas ACAT2 is present only in hepatocytes and in intestinal mucosal cells [17].
• We conclude that under various pathologic conditions, fully differentiated macrophages express ACAT2 in addition to ACAT1 [18].
• ACAT1 is ubiquitously expressed, whereas ACAT2 is primarily expressed in intestinal mucosa and plays an important role in intestinal cholesterol absorption [19].

Associations of ACAT1 with chemical compounds

• Pactimibe exhibited dual inhibition for ACAT1 and ACAT2 (concentrations inhibiting 50% [IC50s] at micromolar levels) more potently than avasimibe [20].
• These results suggest that ACAT1/2 dual inhibitor pactimibe has anti-atherosclerotic potential beyond its plasma cholesterol-lowering activity [20].
• Known ACAT inhibitors, pyripyropene A, oleic acid anilide, and diethyl pyrocarbonate, were tested to evaluate the inhibitory specificity and sensitivity of the expressed enzymes [15].
• Furthermore, cholesterol was more rapidly utilized by hACAT-1, but hACAT-2 esterified other cholic acid derivatives more efficiently [15].
• Human ACAT inhibitory effects of shikonin derivatives from Lithospermum erythrorhizon [16].

Other interactions of ACAT1

• Physiologically the two mitochondrial enzymes have different roles: SCOT mediates energy production from ketone bodies (ketolysis), whereas T2 functions both in ketogenesis and ketolysis [21].
• Genes studied encompass both novel candidates as well as several recently claimed to be associated with AD (e.g. urokinase plasminogen activator (PLAU) and acetyl-coenzyme A acetyltransferase 1 (ACAT1)) [22].
• Conversely, deleting this motif from the full-length ACAT1 converted the enzyme from a homotetramer to a homodimer [23].
• Activities of 3-hydroxybutyrate dehydrogenase, 3-oxoacid CoA-transferase and acetoacetyl-CoA thiolase in relation to ketone-body utilisation in muscles from vertebrates and invertebrates [24].
• Deficiency of beta-ketothiolase (beta-KT, also known as T2, mitochondrial acetoacetyl-CoA thiolase and acetyl-CoA acetyltransferase 1) is a well-described disorder which presents with acute episodic ketoacidosis [25].

Analytical, diagnostic and therapeutic context of ACAT1

• Furthermore, RT-PCR clearly revealed the presence of both ACAT1 and ACAT2 mRNAs in human atherosclerotic aorta [18].
• The expressed hACAT-1 and hACAT-2 appeared as a 50 kDa- and a 46 kDa-band on SDS-PAGE, respectively, from Hi5 cells and they preferred to exist in oligomeric form, from dimer to tetramer, during the purification process [15].
• Sequence analysis of an isolated, full-length clone of ACAT2 cDNA identified an open reading frame encoding a 526-amino acid protein with essentially no sequence similarity to the ACAT1 cDNA over the N-terminal 101 amino acids but with 57% identity predicted over the remaining 425 amino acids [26].
• The expression of ACAT1 and ACAT2 was measured by TaqMan real-time quantitative PCR normalized to 18s ribosomal RNA [27].
• Western blot analysis also showed a higher level of ACAT1 protein in the duodenum of high responders than in that of low responders [27].

References