• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • ACAT may act as a dimer of dimer


    ACAT1 may act as a dimer of dimer [38]. Within each dimer, it may contain two identical sterol substrate sites (designated as site S), and one or two sterol activator site(s) (designated as site A). Site S preferentially binds pregnenolone (PREG); it can also bind a variety of sterols that contain 3-beta-hydroxy moieties. Site A prefers to bind CHOL but cannot bind PREG; it can also bind a variety of other sterols such as plant sterols, oxysterols, yeast sterol, epi-cholesterol, and ent-CHOL etc. When only PREG is present, PREG binds site S, but it fails to trigger appropriate conformational changes, and the enzyme can only catalyze PREG esterification at a very low rate. When PREG and CHOL (or other sterol analogs) are both present, binding of CHOL at site A causes conformational changes, enabling the enzyme to increase the rate of esterification reaction much more efficiently.
    ACAT and neurosteroid esterification Neurosteroids including the steroids PREG, DHEA, progesterone and allopregnanolone etc., are synthesized de novo in the brain by neurons and astrocytes, or are produced in peripheral tissues but accumulate in the central nervous system [39,40]. Various neurosteroids possess many interesting biological activities. For example, neurosteroids can allosterically regulate gamma-aminobutyric ABT263 sale receptors [41]. PREG sulfate, which contains a sulfate ester at the 3β-hydroxyl moiety, can potentiate the calcium conductivity of the N-methyl-aspartate receptor channels in rat hippocampal and cortical neurons [42,43]. In animal studies, administration of neurosteroids can have beneficial effects on learning and memory behavior [44]. More recently, Vallee et al. [45] reported that free, unesterified PREG present in the rodent brain reduces several effects of the main active principle of Cannabis sativa (marijuana), Δ9 tetrahydrocannabinol. This result suggests that PREG can protect the brain from type-1 cannabinoid over-activation, which may have implications for drug intoxication and addiction. In rodent brains, the concentration of free PREG ranges from 2 to 13ng/g wet brain weight [46]. PREG sulfate levels are almost undetectable, while PREG fatty acyl ester levels are higher [47]. In mouse brain, ACAT1 protein expression and its enzymatic activity has been demonstrated [3]. However, whether ACAT1 is involved in fatty acylation of PREG in the central nervous system remains to be demonstrated.
    ACAT and oxysterol esterification Cholesterol is the precursor for various oxidized sterols, such as: 7α-hydroxycholesterol, 22(R)-hydroxycholesterol, 24(S)-hydroxcholesterol, 25-hydroxycholesterol and 27-hydroxycholesterol [48]. 7α-hydroxycholesterol is the obligatory precursor for bile acid biosynthesis. 22(R)-hydroxycholesterol is the obligatory sterol intermediate in order to form PREG. 24(S)-hydroxycholesterol is the major oxysterol present in the brain, and plays important role in mediating the excretion of cholesterol from the brain [49]. Other oxysterols are involved in regulation of numerous cellular processes [50,51] including sterol synthesis, DNA synthesis, cell growth, proliferation, cell death, etc. In the plasma, significant portions of 24(S)-hydroxycholesterol, 25-hydroxycholesterol and 27-hydroxycholesterol can all be converted into fatty acyl esters through the enzyme LCAT [52]. In macrophages, Freeman et al. [53,54] showed that certain oxysterols added to growth medium led to cell apoptosis; blocking ACAT enzyme activity with ACAT inhibitors, or with genetic ablation of ACAT1, significantly increased macrophage apoptosis. These results show that oxysteryl esters formed by ACAT1 play important role in mediating apoptosis in macrophages in culture. In a different cell system, Lu et al. [55] reported that in human Huh7 and HepG2 cells, adding a selective ACAT2 inhibitor, but not a selective ACAT1 inhibitor, caused significant reduction in the secretion of oxysteryl esters (27-hydroxycholesterol, 24(S)-hydroxycholesterol). ACAT2 inhibition also led to a significant increase in the cellular oxysteryl ester concentration, suggesting that blocking ACAT2 led to increased esterification of oxysterols by ACAT1.