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Cholestatic hepatitis is frequently found in Niemann-Pick C (NPC) disease. We studied the influence of diet and the low density lipoprotein receptor (LDLR, Ldlr in mice, known to be the source of most of the stored cholesterol) on liver disease in the mouse model of NPC. [Npc1.sup.-/-] mice of both sexes, with or without the Ldlr knockout, were fed a 18% fat, 1% cholesterol ('high-fat') diet and were evaluated by chemical and histological methods. Bile acid transporters [multidrug resistance protein (Mrps) 1-5; Ntcp, Bsep, and OatP1, 2, and 4] were quantitated by real-time RT-PCR. Many mice died prematurely (within 6 wk) with hepatomegaly. Histopathology showed an increase in macrophage and hepatocyte lipids independent of Ldlr genotype. Non-zone-dependent diffuse fibrosis was found in the surviving mice. Serum alanine aminotransferase was elevated in [Npc1.sup.-/-] mice on the regular diet and frequently became markedly elevated with the high-fat diet. Serum cholesterol was increased in the controls but not the [Npc1.sup.-/-] mice on the high-fat diet; it was massively increased in the [Ldlr.sup.-/-] mice. Esterified cholesterol was greatly increased by the high-fat diet, independent of Ldlr genotype. 7-Glutamyltransferase was also elevated in [Npc.sup.1-/-] mice, more so on the high-fat diet. Mrps 1-5 were elevated in [Npc1.sup.-/-] liver and became more elevated with the high-fat diet; Ntcp, Bsep, and OatP2 were elevated in [Npc1.sup.-/-] liver and were suppressed by the high-fat diet. In conclusion, [Npc1.sup.-/-] mice on a high-fat diet provide an animal model of NPC cholestatic hepatitis and indicate a role for altered bile acid transport in its pathogenesis. Niemann-Pick C; low density lipoprotein receptor knockout; neonatal cholestasis; bile acid transporters; non-zone-dependent fibrosis

The neuropeptide leptin has been shown to selectively modulate rat chorda tympani (CT) responses to sweet tastants. To explore whether other neuropeptides can modulate such responses, rat whole nerve CT responses to NaCl, HCl, quinine HCl, and sucrose were measured while administering cholecystokinin-8 (CCK-8), substance [P.sub.4-11] ([SP.sub.4-11]), or calcitonin gene-related peptide (CGRP). To avoid possible confounding effects on CT responses that take long times to develop, such as those that arise from intraperitoneal injections, we investigated the effects of the above peptides injected into the ipsilateral lingual artery (LA) on CT nerve responses during the initial seconds after a tastant was placed on the tongue. We found that CT responses to NaCl and HCl were increased by CCK-8 and decreased by CGRP. [SP.sub.4-11] had no noticeable effect. Peptide-induced CT responses to quinine HCl or sucrose were too small to accurately detect. These data suggest that at short latencies, after local infusion via the LA, neuropeptides can alter CT responses in a peptide-specific manner. taste; cholecystokinin; calcitonin gene-related peptide; substance P; lingual artery