Disease relevance of ACAT2

• We identified hepatic nuclear factor 1 (HNF1) as an important liver-specific trans-acting element for the human ACAT2 gene using the human hepatocellular carcinoma cell lines HuH7 and HepG2 [1].
• At the present time, the bulk of the available data suggest that the strategy seeming to bear the most potential for treatment of coronary heart disease associated with hypercholesterolemia would be to specifically inhibit ACAT2 [2].
• A detailed kinetic characterization of the cytosolic acetoacetyl-CoA thiolase in liver, subcutaneous adipose tissue, and cultured fibroblasts of a patient with severe neurologic symptoms showed this enzyme to be much more sensitive to inhibition by CoA than that enzyme of normal human liver [3].

Psychiatry related information on ACAT2

• Biochemical investigations on a patient with a defect in cytosolic acetoacetyl-CoA thiolase, associated with mental retardation [4].

High impact information on ACAT2

• This chromosomal region harbors positional candidate genes, such as the insulin-like growth factor 2 receptor (IGF2R, 6q26) and acetyl-CoA acetyltransferase 2 (ACAT2, 6q25.3-q26) [5].
• Possible strategies focused on selective ACAT 2 inhibition or the combination of ACAT inhibitors with compounds that stimulate reverse cholesterol transport may prove to have clinical benefit [6].
• Two ACAT genes (ACAT1 and ACAT2) have been identified [7].
• Each tagged ACAT2 was expressed in the endoplasmic reticulum as a single undegraded protein band and was at least partially active enzymatically [7].
• The enzymology of VLDL triglyceride synthesis is still poorly understood; however, it appears that ACAT2 is the sole source of cholesterol esters for VLDL and chylomicron assembly [8].

Biological context of ACAT2

• Targeted deletion of the HNF1 binding site in the DNA sequence abolished not only the basal promoter function in HepG2 and HuH7 cells but also the induction of the ACAT2 promoter by HNF1 [1].
• Much has been learned from mice with gene deletions for either ACAT1 or ACAT2 [2].
• These two cell types have an abundance of additional mechanisms for disposing of cholesterol so that depletion of ACAT2 does not signal apoptosis [2].
• The primate ACAT2 gene product was cloned from an African green monkey liver cDNA library [9].
• Topologic predictions from the amino acid sequence of ACAT2 indicates that it has seven trans-membrane domains in a configuration that places the putative active site of the enzyme in the lumen of the endoplasmic reticulum [9].

Anatomical context of ACAT2

• In adult humans, ACAT1 is present in most tissues, whereas ACAT2 is localized to enterocytes and hepatocytes [1].
• Neither flavonoid demonstrated selective inhibition of either form of acyl CoA:cholesterol acyltransferase (ACAT) as determined using CHO cells stably transfected with either ACAT1 or ACAT2 [10].
• Practical assay method of cytosolic acetoacetyl-CoA thiolase by rapid release of cytosolic enzymes from cultured lymphocytes using digitonin [11].
• ACAT-1 is more involved in macrophage foam cell formation and ACAT-2 plays a critical role in the cholesterol absorption process in intestinal enterocytes [12].

Associations of ACAT2 with chemical compounds

• Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP [10].
• A critical role for the histidine residues in the catalytic function of acyl-CoA:cholesterol acyltransferase catalysis: evidence for catalytic difference between ACAT1 and ACAT2 [13].
• Pactimibe exhibited dual inhibition for ACAT1 and ACAT2 (concentrations inhibiting 50% [IC50s] at micromolar levels) more potently than avasimibe [14].
• Here, we describe the high resolution structure of human cytosolic acetoacetyl-CoA thiolase (CT), both unliganded (at 2.3 angstroms resolution) and in complex with CoA (at 1.6 angstroms resolution) [15].
• We designed a simple approach to determine cytosolic acetoacetyl-CoA thiolase (CT) activity for differential diagnosis of ketone body catabolic defects, using rapid cell-subfractionation of cultured lymphocytes with digitonin [11].

Physical interactions of ACAT2

• Electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that the transcription factors HNF1alpha and HNF1beta interact with this region in the human ACAT2 gene in vitro and in vivo [1].

Other interactions of ACAT2

• To study ACAT2 topology, we inserted two different antigenic tags (hemagglutinin, monoclonal antibody Mab1) at various hydrophilic regions flanking each of its predicted TMDs, and expressed the recombinant proteins in mutant Chinese hamster ovary cells lacking endogenous ACAT [7].
• Control of ACAT2 liver expression by HNF1 [1].

Analytical, diagnostic and therapeutic context of ACAT2

• Northern blot analysis showed that the ACAT2 mRNA was expressed primarily in liver and intestine in monkeys [9].
• 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 [9].

References