ABSTRACT
To address the role of the noncatalytic ligand function of hepatic lipase (HL) in low density lipoprotein (LDL) receptor-mediated lipoprotein metabolism, we characterized transgenic mice lacking the LDL receptor (LDLR) that express either catalytically active (Ldlr(-/-)HL) or inactive (Ldlr(-/-)HL(S145G)) human HL on both chow and high fat diets and compared them with nontransgenic Ldlr(-/-) mice. In mice fed a chow diet, apolipoprotein (apo)B-containing lipoprotein levels were 40-60% lower in Ldlr(-/-)HL and Ldlr(-/-)HL(S145G) mice than in Ldlr(-/-) mice. This decrease was mainly reflected by decreased apoB-48 levels in the Ldlr(-/-)HL mice and by decreased apoB-100 levels in Ldlr(-/-) HL(S145G) mice. These findings indicate that HL can reduce apoB-100-containing lipoproteins through a noncatalytic ligand activity that is independent of the LDLR. Cholesterol enrichment of the apoB-containing lipoproteins induced by feeding Ldlr(-/-)HL and Ldlr(-/-)HL(S145G) mice a cholesterol-enriched high fat (Western) diet resulted in parallel decreases in both apoB-100 and apoB-48 levels, indicating that HL is particularly efficient at reducing cholesterol-enriched apoB-containing lipoproteins through both catalytic and noncatalytic mechanisms. These data suggest that the noncatalytic function of HL provides an alternate clearance pathway for apoB-100- and apoB-48-containing lipoproteins that is independent of the LDLR and that contributes to the clearance of high density lipoproteins.
Subject(s)
Lipase/metabolism , Lipoproteins, LDL/metabolism , Liver/enzymology , Receptors, LDL/physiology , Animal Feed , Animals , Apolipoprotein B-100 , Apolipoprotein B-48 , Apolipoproteins B/blood , Blotting, Western , Catalysis , Diet , Humans , Lipoproteins, LDL/blood , Mice , Mice, Transgenic , Receptors, LDL/genetics , Triglycerides/bloodABSTRACT
In a phase II study in patients with small cell lung cancer (SCLC) the combination of cyclophosphamide, cisplatinum and etoposide was found to be active, the response rate was 91% (30% CR, 61% PR) in the whole group. In 40 limited disease patients 19 CR (48%) and 20 PR (50%) were seen, whereas in 30 extensive disease patients only 2 CR (7%) and 23 PR (77%) were reached. Adding a second combination of doxorubicin, vincristine and procarbazine resulted in response improvement in only two patients. Median response duration was 41 weeks in CR patients and 30 in PR patients (p less than 0.01). Median survival was 66 in CR and 45 weeks in PR patients (p less than 0.002). Performance score and disease stage were found to be good prognostic factors. Four patients (6%) are disease-free at 2 1/2 years. The value of sequential chemotherapy for SCLC is probably minimal in view of the lack of response improvement.