Hepatic Niemann–Pick C1-like 1

Pramfalk, Camilla; Jiang, Zhaoyan; Parini, Paolo

doi:10.1097/mol.0b013e3283468c28

Cited by 24 publications

(17 citation statements)

References 58 publications

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“…This change is associated with a marked reduction in hepatic Abcg5 and Abcg8 mRNAs, which encode two key half-transporters that mediate cholesterol efflux into the bile (25,26). Collectively, these changes are likely to be the major factors in the excess cholesterol accumulation in the LdlrϪ/ϪxLcatϩ/ϩ liver.…”

Section: Discussionmentioning

confidence: 99%

Lecithin:Cholesterol Acyltransferase Deficiency Protects against Cholesterol-induced Hepatic Endoplasmic Reticulum Stress in Mice

Hager

Pun

et al. 2012

Journal of Biological Chemistry

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Background: Hepatic ER stress promotes insulin resistance, but the role of cholesterol in this pathway is unknown. Results: LCAT-deficient mice maintain a low ER cholesterol and are protected from cholesterol-induced ER stress. Conclusion: ER cholesterol, not tissue cholesterol, is crucial for hepatic ER stress development. Significance: Modulators of hepatic ER cholesterol may be novel targets to treat diabetes.

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Section: Discussionmentioning

confidence: 99%

Lecithin:Cholesterol Acyltransferase Deficiency Protects against Cholesterol-induced Hepatic Endoplasmic Reticulum Stress in Mice

Hager

Pun

et al. 2012

Journal of Biological Chemistry

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“…This remains to be fully characterized, but regardless, we describe that blocking NPC1L1 with ezetimibe in a rodent model effectively suppresses GRA-induced hypercholesterolemia . We postulate that coadministering GRAs and ezetimibe will work equally well, or better, in humans because, unlike the exclusive expression of Npc1l1 in intestine in mice, NPC1L1 is expressed abundantly in the liver and intestine in humans ( 58 ), and ezetimibe exerts its lipid-lowering effect by blocking NPC1L1 in both the liver and intestine in humans ( 59 ).…”

Section: Discussionmentioning

confidence: 99%

Glucagon receptor antagonism induces increased cholesterol absorption

Guan

Yang

et al. 2015

Journal of Lipid Research

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“…Although murine livers express G5G8 but not NPC1L1, human livers express appreciable amounts of both ( 52,53 ), which can again function as another layer of protection against any toxicity of phytosterols. The data show that the G5G8 Ϫ / Ϫ livers accumulated phytosterols in both the free and ester forms, whereas livers of mice with intact G5G8 had almost undetectable concentrations of these sterols (supplemental Fig.…”

Section: G5g8mentioning

confidence: 99%

ACAT2 and ABCG5/G8 are both required for efficient cholesterol absorption in mice: evidence from thoracic lymph duct cannulation

Nguyen

Sawyer

Kelley

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org Beginning in 1974, the identifi cation of sitosterolemia ( 1 ), a rare recessive disorder characterized by elevated plasma and tissue concentrations of phytosterols, has focused attention on the basic molecular processes that govern how the body normally absorbs animal-derived dietary cholesterol while excluding all other similarly structured plantderived sterols, generally called phytosterols. Phytosterols, including campesterol, stigmasterol, and sitosterol, differ from cholesterol mainly in possessing one or two additional carbons in side chains at C24. The average North American diet contains about equal amounts of cholesterol and phytosterols ( ‫ف‬ 150-400 mg/day) ( 2-5 ), yet <5% of phytosterols are absorbed compared with ‫ف‬ 50% of cholesterol ( 4, 6 ). Thus in healthy individuals, sensitive mechanisms exist that allow the body to distinguish among modestly different sterol structures.In general, different species of sterols have different absorption effi ciencies; the closer the structural similarity to the cholesterol molecule, the higher the percentage absorption ( 4, 7 ). Even mildly hypercholesterolemic patients have serum concentrations of phytosterols that are 500 (campesterol) to 20,000 (sitosterol) times lower than that of cholesterol. Patients with sitosterolemia have increased fractional sterol absorption rates and impaired biliary secretion of neutral sterols, resulting in accumulations of these sterols in the blood and tissues ( 1, 8 ), premature atherosclerosis, and tendon/skin xanthomatosis ( 8, 9 ). Sitosterolemia has been linked to mutations in either adenosine triphosphate-binding cassette transporter G5 or G8 Abstract The metabolic fate of newly absorbed cholesterol and phytosterol is orchestrated through adenosine triphosphate-binding cassette transporter G5 and G8 heterodimer (G5G8), and acyl CoA:cholesterol acyltransferase 2 (ACAT2). We hypothesized that intestinal G5G8 limits sterol absorption by reducing substrate availability for ACAT2 esterifi cation and have attempted to defi ne the roles of these two factors using gene deletion studies in mice. Male ACAT2 ؊ / ؊ mice, whereas it was up to 6.8% in G5G8؊ / ؊ and DKO mice. G5G8 ؊ / ؊ mice also produced chylomicrons with ‫ف‬ 70% less cholesterol ester mass than WT mice. In contrast to expectations, the data demonstrated that the absence of G5G8 led to decreased intestinal cholesterol esterifi cation and reduced cholesterol transport efficiency. Intestinal G5G8 appeared to limit the absorption of phytosterols; ACAT2 more effi ciently esterifi ed cholesterol than phytosterols. The data indicate that handling of sterols by the intestine involves both G5G8 and ACAT2 but that an additional factor (possibly Niemann-Pick C1-like 1) may be key in determining absorption effi ciency. Abbreviations: ATF-6, activating transcription factor 6; CE, cholesterol ester; DDIT-3, DNA damage-inducible transcript 3; ER, endoplasmic reticulum; FC, free cholesterol; FP, free phytosterol; G5G8, adenosin...

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Hepatic Niemann–Pick C1-like 1

Abstract: Evidence suggests the involvement of NPC1L1 in biliary cholesterol uptake, HDL metabolism and cholesterol gallstone disease. Although difficult, studies in humans are required to further elucidate the function of this protein in the liver.

Cited by 24 publications

References 58 publications

Lecithin:Cholesterol Acyltransferase Deficiency Protects against Cholesterol-induced Hepatic Endoplasmic Reticulum Stress in Mice

Lecithin:Cholesterol Acyltransferase Deficiency Protects against Cholesterol-induced Hepatic Endoplasmic Reticulum Stress in Mice

Glucagon receptor antagonism induces increased cholesterol absorption

ACAT2 and ABCG5/G8 are both required for efficient cholesterol absorption in mice: evidence from thoracic lymph duct cannulation

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