Correlation between serum levels of some cholesterol precursors and activity of HMG-CoA reductase in human liver

Björkhem, Ingemar; Miettinen, T. A.; Reihnér, Eva; Ewerth, S; Angelin, Bo; Einarsson, Kurt

doi:10.1016/s0022-2275(20)38603-x

Cited by 244 publications

(24 citation statements)

References 9 publications

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“…This excludes the unlikely event that MVA levels increased in response to inhibition of one or more steps in the conversion of mevalonate to cholesterol. In particular, both indices reflect predominantly hepatic HRase activity (37,41). These results are compatible with the genetic data that conclusively demonstrate that the primary defect in sitosterolemia does not involve the HRase locus.…”

Section: Discussionsupporting

confidence: 89%

“…Thus there is good evidence that fasting plasma MVA levels provide a valid albeit semi-quantitative index of cholesterol synthesis. The concentration of 7-lathosterol in plasma is another well-established index of whole body cholesterol synthesis in humans (25,39,40) that has been shown to correlate closely with hepatic HRase activity (41). Serum lathosterol concentration and the L/C ratio both increase during treatment with cholestyramine or colestipol (42,43), which stimulate cholesterol biosynthesis in the liver, and decrease during treatment with an HMG-CoA reductase inhibitor (25,42,44).…”

Section: Discussionmentioning

confidence: 99%

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HMG-CoA reductase is not the site of the primary defect in phytosterolemia

Berger

Pegoraro

Patel

et al. 1998

Journal of Lipid Research

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Phytosterolemia is an autosomal recessive disorder characterized by the excessive absorption, reduced excretion, and consequent high tissue and plasma levels of plant sterols, by the presence of tendon xanthomas, and by premature atherosclerosis. Low HMG-CoA reductase (HRase) activity and mass have been reported in liver and mononuclear leucocytes and low mRNA levels in liver from phytosterolemic subjects. These results led to the proposal that the primary defect in this condition involves the HRase gene locus. We examined this hypothesis in phytosterolemic subjects and heterozygous parents from four unrelated families. A variable number tandem repeat (VNTR) polymorphism of the HRase gene in the three informative families and a ScrFI restriction fragment length polymorphism (RFLP) within intron 2 of the gene in one of these families, segregated independently of the disease phenotype. Biological parentage was confirmed in the family in whom both polymorphisms failed to segregate with the disorder. These results conclusively exclude the HRase gene locus as the site of the primary defect in phytosterolemia. The study was extended by examining plasma levels of mevalonic acid and lathosterol, both markers of cholesterol biosynthesis, in response to cholestyramine, a bile acid sequestrant that is known to up-regulate HRase. Oral administration of cholestyramine resulted in a substantial (7.7-fold) increase in mevalonic acid levels in two phytosterolemic subjects, compared with a 2.2-fold rise in their obligate heterozygote parents and a 2.3-fold increase in three healthy control subjects. The lathosterol/cholesterol (L/C) ratio showed a quantitatively similar response. Baseline levels of mevalonate and the L/C ratio were low in the phytosterolemic patients in conformity with reports of reduced cholesterol biosynthesis and HRase activity in this disorder. These functional data provide support for the concept that the primary defect in phytosterolemia does not affect a trans gene locus responsible for the constitutive expression or regulation of HMG-CoA reductase.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

HMG-CoA reductase is not the site of the primary defect in phytosterolemia

Berger

Pegoraro

Patel

et al. 1998

Journal of Lipid Research

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“…Rifampicin increased lathosterol to cholesterol ratio (Figure 2b), a surrogate marker for cholesterol synthesis (Björkhem et al, 1987).…”

Section: Rifampicin Affects Fasting Serum Metabolomics By Increasing mentioning

confidence: 98%

Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2‐mediated mechanism

Karpale

Käräjämäki

Kummu

et al. 2021

British J Pharmacology

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Background and Purpose: Many drugs and environmental contaminants induce hypercholesterolemia and promote the risk of atherosclerotic cardiovascular disease.We tested the hypothesis that pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, regulates the level of circulating atherogenic lipids in humans and utilized mouse experiments to identify the mechanisms involved.Experimental Approach: We performed serum NMR metabolomics in healthy volunteers administered rifampicin, a prototypical human PXR ligand or placebo in a crossover setting. We used high-fat diet fed wild-type and PXR knockout mice to investigate the mechanisms mediating the PXR-induced alterations in cholesterol homeostasis.

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“…Our results show abnormalities in sterol homeostasis markers. Lathosterol is the most reliable surrogate marker of de novo liver cholesterol synthesis [39], which can be produced in other tissues but does not pass into the bloodstream; hence, it is considered to be liver-specific [40,41]. Higher lathosterol concentrations may be directly related to CFTR mutations.…”

Section: Discussionmentioning

confidence: 99%

Severe Genotype, Pancreatic Insufficiency and Low Dose of Pancreatic Enzymes Associate with Abnormal Serum Sterol Profile in Cystic Fibrosis

Drzymała-Czyż

Krzyżanowska-Jankowska

Dziedzic

et al. 2021

Biomolecules

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Background: Several factors could lead to lipid disturbances observed in cystic fibrosis (CF). This study aimed to assess sterol homeostasis in CF and define potential exogenous and endogenous determinants of lipid dysregulation. Methods: The study involved 55 CF patients and 45 healthy subjects (HS). Sterol concentrations (μg/dL) were measured by gas chromatography/mass spectrometry. CF was characterised by lung function, pancreatic status, liver disease and diabetes coexistence, Pseudomonas aeruginosa colonisation and BMI. CFTR genotypes were classified as severe or other. Results: Campesterol and β-sitosterol concentrations were lower (p = 0.0028 and p < 0.0001, respectively) and lathosterol levels (reflecting endogenous cholesterol biosynthesis) were higher (p = 0.0016) in CF patients than in HS. Campesterol and β-sitosterol concentrations were lower in patients with a severe CFTR genotype, pancreatic insufficiency and lower pancreatic enzyme dose (lipase units/gram of fat). In multiple regression analyses, β-sitosterol and campesterol concentrations were predicted by genotype and pancreatic insufficiency, whereas cholesterol and its fractions were predicted by phytosterol concentrations, age, dose of pancreatic enzymes, nutritional status and genotype. Conclusions: Independent determinants of lipid status suggest that malabsorption and pancreatic enzyme supplementation play a significant role in sterol abnormalities. The measurement of campesterol and β-sitosterol concentrations in CF patients may serve for the assessment of the effectiveness of pancreatic enzyme replacement therapy and/or compliance, but further research is required.

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Correlation between serum levels of some cholesterol precursors and activity of HMG-CoA reductase in human liver

Cited by 244 publications

References 9 publications

HMG-CoA reductase is not the site of the primary defect in phytosterolemia

HMG-CoA reductase is not the site of the primary defect in phytosterolemia

Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2‐mediated mechanism

Severe Genotype, Pancreatic Insufficiency and Low Dose of Pancreatic Enzymes Associate with Abnormal Serum Sterol Profile in Cystic Fibrosis

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