In a subgroup of children with chronic active hepatitis, circulating autoantibodies occur that bind to liver and kidney endoplasmic reticulum (anti-liver/kidney microsome antibody type I or anti-LKM1). Anti-LKM1 titers follow the severity of the disease and the presence of these antibodies serves as a diagnostic marker for this autoimmune hepatitis type II. We demonstrate that anti-LKM1 IgGs specifically inhibit the hydroxylation of bufuralol in human liver microsomes. Using two assay systems with different selectivity for the two cytochrome P-450 isozymes catalyzing bufuralol metabolism in human liver, we show that anti-LKM1 exclusively recognizes cytochrome P-450dbl. Immunopurification of the LKM1 antigen from solubilized human liver microsomes resulted in an electrophoretically homogenous protein that had the same molecular mass (50 kDa) as purified P-450dbl and an identical N-terminal amino acid sequence. Recognition of both purified P-450dbl and the immunoisolated protein on western blots by several monoclonal antibodies confirmed the identity of the LKM1 antigen with cytochrome P-450dbl. Cytochrome P-450dbI has been identified as the target of a common genetic polymorphism of drug oxidation. However, the relationship between the polymorphic cytochrome P-450dbl and the appearance of anti-LKM1 autoantibodies as well as their role in the pathogenesis of chronic active hepatitis remains speculative.
The core of the SP is made of aggregated amyloid- (A  ) peptide. A  peptide is cleaved from a type 1 transmembrane protein, the amyloid protein precursor (APP), by the sequential activities of the  and ␥ secretases. Special staining of microscopic sections from brain samples of AD patients has long suggested that SPs were enriched in lipids ( 5 ). The presence of cholesterol among those lipids is plausible since apolipoprotein E (apoE), a transporter of cholesterol, has been found in the SPs by immunohistochemistry ( 6, 7 ). The apo 4 allele is currently considered as the risk factor best associated with AD ( 8 ). Although the role of cholesterol has remained elusive, a much debated meta-analysis has shown that the use of statins, which inhibit cholesterol synthesis, was associated with a decreased prevalence of AD ( 9, 10 ). In cell cultures, the interaction between APP and cholesterol metabolism has been found so intricate that APP has been considered a sensor modulating the cholesterol content of the cell membrane ( 11 ).Histological studies have apparently confi rmed the cholesterol enrichment of the SPs in transgenic mice and AD patients ( 12 ). Two methods have been used. 1 ) Filipin, a well-known fl uorescent probe of membrane cholesterol, labels the SPs and subsequently resists the photobleaching that rapidly decreases the fl uorescence of the surrounding tissue. 2 ) An enzymatic technique based upon cholesterol oxidase activity was initially devised (and commercialized) for colorometric cholesterol assay (not for histochemistry). It is based on the oxidation of Amplex Red ® (10-acetyl-3,7-dihydroxyphenoxazine) into brightly fl uorescent resorufi n. Press, September 18, 2009 DOI 10.1194 Abbreviations: A  , amyloid- peptide; AD, Alzheimer's disease; apoE, apolipoprotein E; APP, amyloid protein precursor; LCM, laser capture microdissection; LC-MS, liquid chromatography coupled with mass spectrometry; LRP, low density lipoprotein receptor-related protein; SP, senile plaque. Published, JLR Papers in
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