Altered expression of apoA-I, apoA-IV and PON-1 activity in CBS deficient homocystinuria in the presence and absence of treatment: possible implications for cardiovascular outcomes

Mol Genet Metab. 2012 Sep;107(1-2):55-65. doi: 10.1016/j.ymgme.2012.04.025. Epub 2012 May 5.


Classical homocystinuria (HCU) is caused by mutations in cystathionine beta-synthase (CBS) which, if untreated, typically results in cognitive impairment, thromboembolic complications and connective tissue disturbances. Paraoxonase-1 (PON1) and apolipoprotein apoA-I are both synthesized in the liver and contribute to much of the cardioprotective effects of high density lipoprotein. Additionally, apoA-I exerts significant neuro-protective effects that act to preserve cognition. Previous work in a Cbs null mouse model that incurs significant liver injury, reported that HCU dramatically decreases PON1 expression. Conflicting reports exist in the literature concerning the relative influence of homocysteine and cysteine upon apoA-I expression. We investigated expression of PON1 and apoA-I in the presence and absence of homocysteine lowering therapy, in both the HO mouse model of HCU and human subjects with this disorder. We observed no significant change in plasma PON1 paraoxonase activity in either mice or humans with HCU indicating that this enzyme is unlikely to contribute to the cardiovascular sequelae of HCU. Plasma levels of apoA-I were unchanged in mice with mildly elevated homocysteine due to CBS deficiency but were significantly diminished in both mice and humans with HCU. Subsequent experiments revealed that HCU acts to dramatically decrease apoA-I levels in the brain. Cysteine supplementation in HO mice had no discernible effect on plasma levels of apoA-I while treatment to lower homocysteine normalized plasma levels of this lipoprotein in both HO mice and humans with HCU. Our results indicate that plasma apoA-I levels in HCU are inversely related to homocysteine and are consistent with a plausible role for decreased expression of apoA-I as a contributory factor for both cardiovascular disease and cognitive impairment in HCU.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Apolipoprotein A-I / blood
  • Apolipoprotein A-I / metabolism*
  • Apolipoproteins A / blood
  • Apolipoproteins A / metabolism*
  • Aryldialkylphosphatase / blood
  • Aryldialkylphosphatase / metabolism*
  • Betaine / therapeutic use
  • Brain / drug effects
  • Brain / metabolism
  • Carboxylic Ester Hydrolases / blood
  • Child
  • Child, Preschool
  • Dietary Supplements
  • Disease Models, Animal
  • Homocysteine / blood
  • Homocystinuria / diet therapy
  • Homocystinuria / drug therapy
  • Homocystinuria / metabolism*
  • Humans
  • Lipotropic Agents / therapeutic use
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Young Adult


  • Apolipoprotein A-I
  • Apolipoproteins A
  • Lipotropic Agents
  • apolipoprotein A-IV
  • Homocysteine
  • Betaine
  • Carboxylic Ester Hydrolases
  • arylesterase
  • Aryldialkylphosphatase