Niemann‐Pick C2 Protein Expression Regulates Lithogenic Diet‐Induced Gallstone Formation and Dietary Cholesterol Metabolism in Mice

Balboa, Elisa; Morales, Gabriela; Aylwin, Paula; Carrasco, Gonzalo; Amigo, Ludwig; Castro, Juan Francisco; Rigotti, Attilio; Zanlungo, Silvana

doi:10.1007/s11745-011-3625-2

Cited by 6 publications

(4 citation statements)

References 46 publications

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“…Niemann-Pick proteins of class C2 (NPC2) are present in all vertebrates, where they act as carriers for cholesterol and lipids. Serious diseases are related to their absence or malfunctioning (Bjurulf et al, 2008 ; Griese et al, 2010 ; Balboa et al, 2012 ; Frolov et al, 2013 ). A single gene is generally expressed in each vertebrate species (Storch and Xu, 2009 ) with identical amino acids of about 75% among mammals and of 55–70% across vertebrate classes.…”

Section: Introductionmentioning

confidence: 99%

Niemann-Pick C2 Proteins: A New Function for an Old Family

et al. 2018

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Niemann-Pick proteins type C2 (NPC2) are carriers of cholesterol in vertebrates, with a single member in each species. The high sequence conservation between mammals and across vertebrates is related to their common function. In contrast, NPC2 proteins in arthropods have undergone extensive duplication and differentiation, probably under environmental pressure, and are likely to have different functions. Recent studies have suggested that in arthropods these proteins might act as carriers for semiochemicals and other hydrophobic compounds. In this study we focused on the function of a specific NPC2 gene in the moth Helicoverpa armigera (HarmNPC2-1). This protein binds several flavonoids with micromolar dissociation constants. The best ligand was gossypol, present in cotton, one of the main host plants for H. armigera. Western blot revealed the presence of HarmNPC2-1 in different parts of the body, including the antennae, proboscis, and abdomen. In the antennae, in situ hybridization experiments produced strong staining in auxiliary cells at the base of sensilla trichodea, basiconica, coeloconica, and chaetica. Immunocytochemistry confirmed the expression of the protein in sensilla chaetica. Our results support a role of semiochemical carriers for NPC2 proteins in insects and indicate such proteins as new targets for insecticide-free pest population control.

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Section: Introductionmentioning

confidence: 99%

Niemann-Pick C2 Proteins: A New Function for an Old Family

et al. 2018

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“…Thus, this protein may play a crucial role in regulating hepatic cholesterol transport and secretion. Under conditions of feeding the lithogenic diet, biliary cholesterol secretion, gallbladder bile cholesterol saturation, and cholesterol crystal and gallstone formation were reduced in NPC2 hypomorph mice compared with wild‐type mice .…”

Section: Prevention and Dissolution Of Cholesterol Gallstones By Ezetmentioning

confidence: 97%

Prevention of cholesterol gallstones by inhibiting hepatic biosynthesis and intestinal absorption of cholesterol

Wang

Portincasa

Bari

et al. 2013

Eur J Clin Investigation

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Cholesterol cholelithiasis is a multifactorial disease influenced by a complex interaction of genetic and environmental factors, and represents a failure of biliary cholesterol homeostasis in which the physical-chemical balance of cholesterol solubility in bile is disturbed. The primary pathophysiologic event is persistent hepatic hypersecretion of biliary cholesterol, which has both hepatic and small intestinal components. The majority of the environmental factors are probably related to Western-type dietary habits, including excess cholesterol consumption. Laparoscopic cholecystectomy, one of the most commonly performed surgical procedures in the US, is nowadays a major treatment for gallstones. However, it is invasive and can cause surgical complications, and not all patients with symptomatic gallstones are candidates for surgery. The hydrophilic bile acid, ursodeoxycholic acid (UDCA) has been employed as first-line pharmacological therapy in a subgroup of symptomatic patients with small, radiolucent cholesterol gallstones. Long-term administration of UDCA can promote the dissolution of cholesterol gallstones. However, the optimal use of UDCA is not always achieved in clinical practice because of failure to titrate the dose adequately. Therefore, the development of novel, effective, and noninvasive therapies is crucial for reducing the costs of health care associated with gallstones. In this review, we summarize recent progress in investigating the inhibitory effects of ezetimibe and statins on intestinal absorption and hepatic biosynthesis of cholesterol, respectively, for the treatment of gallstones, as well as in elucidating their molecular mechanisms by which combination therapy could prevent this very common liver disease worldwide.

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“…Niemann-Pick C2 (NPC2), a soluble lysosomal protein, is expressed in human and mouse liver and regulates hepatic cholesterol secretion by stimulating Abcg5/g8-mediated cholesterol transport [103]. After secreted into bile [104–106], it promotes cholesterol crystallization and gallstone formation in mice transgenic human NPC2 [107 ▪ ]. In contrast, Npc2 knockout mice show a reduction in hepatic cholesterol secretion and gallstone formation at 2 weeks on a lithogenic diet [106].…”

Section: The Latest Advances In the Pathophysiology Of Gallstones Fromentioning

confidence: 99%

“…After secreted into bile [104–106], it promotes cholesterol crystallization and gallstone formation in mice transgenic human NPC2 [107 ▪ ]. In contrast, Npc2 knockout mice show a reduction in hepatic cholesterol secretion and gallstone formation at 2 weeks on a lithogenic diet [106]. These results imply that biliary proteins could influence gallstone formation by modulating cholesterol crystallization likely through a liquid crystalline pathways in bile [108–111].…”

Section: The Latest Advances In the Pathophysiology Of Gallstones Fromentioning

confidence: 99%

Mouse models of gallstone disease

Wang

Portincasa

Liu

et al. 2018

Current Opinion in Gastroenterology

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Purpose of review The establishment of mouse models of gallstones, and the contribution of mouse models to genetic studies of gallstone disease, as well as the latest advances in the pathophysiology of gallstones from mouse experiments are summarized. Recent findings The combined uses of genomic strategies and phenotypic studies in mice have successfully led to the identification of many Lith genes, which pave the way for the discovery of human LITH genes. The physical–chemical, genetic, and molecular biological studies of gallstone disease in mice with knockout or transgene of specific target genes have provided many novel insights into the complex pathophysiological mechanisms of this very common hepatobiliary disease worldwide, showing that interactions of five primary defects play a critical role in the pathogenesis of cholesterol gallstones. Based on mouse studies, a new concept has been proposed that hepatic hypersecretion of biliary cholesterol is induced by multiple Lith genes, with insulin resistance as part of the metabolic syndrome interacting with cholelithogenic environmental factors to cause the phenotype. Summary The mouse model of gallstones is crucial for elucidating the physical–chemical and genetic mechanisms of cholesterol crystallization and gallstone formation, which greatly increase our understanding of the pathogenesis of this disease in humans.

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Niemann‐Pick C2 Protein Expression Regulates Lithogenic Diet‐Induced Gallstone Formation and Dietary Cholesterol Metabolism in Mice

Cited by 6 publications

References 46 publications

Niemann-Pick C2 Proteins: A New Function for an Old Family

Niemann-Pick C2 Proteins: A New Function for an Old Family

Prevention of cholesterol gallstones by inhibiting hepatic biosynthesis and intestinal absorption of cholesterol

Mouse models of gallstone disease

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