Characterization of liver disease and lipid metabolism in the Niemann‐Pick C1 mouse

Garver, William S.; Jelínek, David; Oyarzo, Janice; Flynn, James M.; Zuckerman, Matthew; Krishnan, Kumar; Chung, Byung Hong; Heidenreich, Randall A.

doi:10.1002/jcb.21200

Cited by 47 publications

(58 citation statements)

References 73 publications

(73 reference statements)

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“…They exhibited increased serum total cholesterol and LDL and HDL levels, whereas findings are variable for the NPC nih mouse, that is, no change, 29 decreased, 18 or increased. 31,32 We also observed fibrosis, which is not observed in chow-fed NPC nih mice 15 but is when NPC nih mice are fed a high-fat diet 17 and in the feline model of NPC disease.…”

Section: Discussionmentioning

confidence: 95%

“…The NPC nih mouse has been shown to exhibit no change, 29 decreases, 18 or increases in serum cholesterol, HDL-cholesterol, 30 and LDL-cholesterol levels. [30][31][32] Knockdown of NPC1 Increases Serum ALT and AST, Indicating Liver Damage.…”

Section: Resultsmentioning

confidence: 99%

“…14 These studies report that NPC nih mice exhibit a liver disease phenotype similar to that seen in the NPC infant. [15][16][17][18][19] Characteristic features include hepatomegaly, liver cholesterol accumulation, increased plasma liver enzymes, and apoptotic cells. 16 Fibrosis occurs when the mice are fed a high-cholesterol diet.…”

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confidence: 99%

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In vivoantisense oligonucleotide reduction of NPC1 expression as a novel mouse model for Niemann Pick type C- associated liver disease

et al. 2008

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Niemann-Pick type C (NPC) is a fatal autosomal recessive lipidosis that is characterized by lysosomal storage of cholesterol and glycosphingolipids. Patients exhibit prolonged neonatal jaundice, hepatosplenomegaly, and progressive neurodegeneration that generally result in death by the teen years. Most clinical cases are caused by mutations in the NPC1 gene. Current mouse models of NPC are not well suited for studying the liver disease due to the rapidly progressing neurological disease. To facilitate study of NPC-associated liver dysfunction, we have developed a novel mouse model using antisense oligonucleotides to ablate NPC1 expression primarily in the liver. Here, we show that the NPC1 knockdown leads to a liver disease phenotype similar to that of patients with NPC and the NPC nih mouse model. Key features include hepatomegaly, lipid storage, elevated serum liver enzymes, and increased apoptosis. Conclusion: This novel NPC1 antisense mouse model will allow delineation of the mechanism by which NPC1 dysfunction leads to liver cell death. (HEPATOLOGY 2008;47:1504-1512

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Section: Discussionmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

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In vivoantisense oligonucleotide reduction of NPC1 expression as a novel mouse model for Niemann Pick type C- associated liver disease

et al. 2008

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“…These results were confirmed and extended using Npc1 heterozygous (Npc1 ?/-) mice, which compared to Npc1 normal (Npc1 ?/? ) and Npc1 homozyous (Npc1 -/-) mice, had livers with an increased expression of caveolin-1 and concentration of triacylglycerol, both of which serve as markers for obesity and diabetes (Garver et al 1997a(Garver et al , 1999(Garver et al , 2007. More recent studies indicate that the Npc1 gene is downregulated by dietary fatty acids, but not dietary cholesterol, through feedback inhibition of the sterol regulatory element-binding protein (SREBP) pathway (Jelinek et al 2012).…”

Section: Obesity Susceptibility Genes That Interact With Dietary Fatsmentioning

confidence: 99%

The genetics of childhood obesity and interaction with dietary macronutrients

et al. 2013

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The genes contributing to childhood obesity are categorized into three different types based on distinct genetic and phenotypic characteristics. These types of childhood obesity are represented by rare monogenic forms of syndromic or non-syndromic childhood obesity, and common polygenic childhood obesity. In some cases, genetic susceptibility to these forms of childhood obesity may result from different variations of the same gene. Although the prevalence for rare monogenic forms of childhood obesity has not increased in recent times, the prevalence of common childhood obesity has increased in the United States and developing countries throughout the world during the past few decades. A number of recent genome-wide association studies and mouse model studies have established the identification of susceptibility genes contributing to common childhood obesity. Accumulating evidence suggests that this type of childhood obesity represents a complex metabolic disease resulting from an interaction with environmental factors, including dietary macronutrients. The objective of this article is to provide a review on the origins, mechanisms, and health consequences of obesity susceptibility genes and interaction with dietary macronutrients that predispose to childhood obesity. It is proposed that increased knowledge of these obesity susceptibility genes and interaction with dietary macronutrients will provide valuable insight for individual, family, and community preventative lifestyle intervention, and eventually targeted nutritional and medicinal therapies.

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“…In human NPC1 carriers, the concentrations of plasma oxysterols, 7-ketocholesterol, and cholestane-3β-5α-6β-triol are commensurately elevated between healthy and NP-C1 levels [14]. The liver in heterozygous Npc1 +/-mice compared with homozygous Npc1 +/+ and presymptomatic Npc1 -/-mice at 35 days of age has an intermediate level of sterol regulatory element-binding transcription factor 1 and 2 protein expression [15]. Subsequent mouse model studies revealed that a high-fat diet promoted greater weight gain, and impaired glucose metabolism and insulin resistance in Npc1 +/-mice [16,17].…”

Section: Introductionmentioning

confidence: 99%

Neurological Dysfunction in Early Maturity of a Model for Niemann–Pick C1 Carrier Status

et al. 2016

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Autosomal recessive inheritance of NPC1 with loss-of-function mutations underlies Niemann-Pick disease, type C1 (NP-C1), a lysosomal storage disorder with progressive neurodegeneration. It is uncertain from limited biochemical studies and patient case reports whether NPC1 haploinsufficiency can cause a partial NP-C1 phenotype in carriers. In the present study, we examined this possibility in heterozygotes of a natural loss-of-function mutant Npc1 mouse model. We found partial motor dysfunction and increased anxiety-like behavior in Npc1 +/-mice by 9 weeks of age.

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Characterization of liver disease and lipid metabolism in the Niemann‐Pick C1 mouse

Cited by 47 publications

References 73 publications

In vivoantisense oligonucleotide reduction of NPC1 expression as a novel mouse model for Niemann Pick type C- associated liver disease

In vivoantisense oligonucleotide reduction of NPC1 expression as a novel mouse model for Niemann Pick type C- associated liver disease

The genetics of childhood obesity and interaction with dietary macronutrients

Neurological Dysfunction in Early Maturity of a Model for Niemann–Pick C1 Carrier Status

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