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Hidden disease susceptibility and sexual dimorphism in the heterozygous knockout of Cyp51 from cholesterol synthesis.

Lewinska M, Juvan P, Perse M, Jeruc J, Kos S, Lorbek G, Urlep Z, Keber R, Horvat S, Rozman D - PLoS ONE (2014)

Bottom Line: Cyp51+/- females fed high-fat, high-cholesterol diet were leaner and had elevated plasma corticosterone compared to controls.The Cyp51+/- females had a modified lipid storage homeostasis protecting them from weight-gain when fed high-fat high-cholesterol diet.Malfunction of one Cyp51 allele therefore initiates disease pathways towards cholesterol-linked liver pathologies and sex-dependent response to dietary challenge.

View Article: PubMed Central - PubMed

Affiliation: Center for Functional Genomics and Bio-Chips, Faculty of Medicine, University of Ljubljana, SI-1000, Ljubljana, Slovenia.

ABSTRACT
We examined the genotype-phenotype interactions of Cyp51+/- mice carrying one functional allele of lanosterol 14α-demethylase from cholesterol biosynthesis. No distinct developmental or morphological abnormalities were observed by routine visual inspection of Cyp51+/- and Cyp51+/+ mice and fertility was similar. We further collected a large data-set from female and male Cyp51+/- mice and controls fed for 16 weeks with three diets and applied linear regression modeling. We used 3 predictor variables (genotype, sex, diet), and 39 response variables corresponding to the organ characteristics (7), plasma parameters (7), and hepatic gene expression (25). We observed significant differences between Cyp51+/- and wild-type mice in organ characteristics and blood lipid profile. Hepatomegaly was observed in Cyp51+/- males, together with elevated total and low-density lipoprotein cholesterol. Cyp51+/- females fed high-fat, high-cholesterol diet were leaner and had elevated plasma corticosterone compared to controls. We observed elevated hepatocyte apoptosis, mitosis and lipid infiltration in heterozygous knockouts of both sexes. The Cyp51+/- females had a modified lipid storage homeostasis protecting them from weight-gain when fed high-fat high-cholesterol diet. Malfunction of one Cyp51 allele therefore initiates disease pathways towards cholesterol-linked liver pathologies and sex-dependent response to dietary challenge.

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Characteristics of knock-out and heterozygous knock-out mouse models.Figure shows mouse characteristics in the cholesterol synthesis (A), bile acid synthesis pathways (B) and lipid transporters (C). In red are marked disease phenotypes, while in green are marked mild/no phenotype. *The heterozygous knock-out models often were not thoroughly investigated. Gene names and references to literature describing mouse models: Acat2 acetyl-coenzyme A acetyltransferase 2; Hmgcs1 3-hydroxy-3-methylglutaryl-coa synthase 1; Hmgcr 3-hydroxy-3-methylglutaryl-coa reductase [55]; Pmvk phosphomevalonate kinase; Mvd diphosphomevalonate decarboxylase; Mvk mevalonate kinase [56]; Idi1 isopentenyl-diphosphate delta isomerase 1; Ggps1 geranylgeranyl diphosphate synthase 1; Fdps farnesyl diphosphate dynthase; Fdft1 farnesyl-diphosphate farnesyltransferase 1 [57]; Sqle squalene epoxidase; Lss lanosterol synthase; Cyp51 lanosterol 14-alpha-demethylase [17], Tm7sf2 C-14 sterol reductase; Lbr lamin-B receptor; Sc4mol methylsterol monooxygenase 1*(WTSI); Nsdhl NAD(P) dependent steroid dehydrogenase-like [58], [59]; Hsd17b7 hydroxysteroid (17-beta) dehydrogenase 7 [60]; Sc5d lathosterol oxidase [61]; Dhcr7 7-dehydrocholesterol reductase [62]; Ebp emopamil binding protein (sterol isomerase) [63]; Dhcr24 24-dehydrocholesterol reductase [41], [64]; Cyp7a1 cholesterol 7-alpha-monooxygenase [65], [66]; Hsd3b7 3 beta-hydroxysteroid dehydrogenase type 7 [67]; Cyp8b1 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase [68]; Cyp27a1 Sterol 26-hydroxylase [69]; Cyp7b1 25-hydroxycholesterol 7-alpha-hydroxylase [70]; Scrab1 scavenger receptor class b, member 1 [71]; Ldlr low density lipoprotein receptor [72]; Cd36 fatty acid translocase [73], [74]; Abcg5 ATP-binding cassette sub-family g member 5; Abcg8 ATP-binding cassette sub-family g member 8 [75].
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pone-0112787-g001: Characteristics of knock-out and heterozygous knock-out mouse models.Figure shows mouse characteristics in the cholesterol synthesis (A), bile acid synthesis pathways (B) and lipid transporters (C). In red are marked disease phenotypes, while in green are marked mild/no phenotype. *The heterozygous knock-out models often were not thoroughly investigated. Gene names and references to literature describing mouse models: Acat2 acetyl-coenzyme A acetyltransferase 2; Hmgcs1 3-hydroxy-3-methylglutaryl-coa synthase 1; Hmgcr 3-hydroxy-3-methylglutaryl-coa reductase [55]; Pmvk phosphomevalonate kinase; Mvd diphosphomevalonate decarboxylase; Mvk mevalonate kinase [56]; Idi1 isopentenyl-diphosphate delta isomerase 1; Ggps1 geranylgeranyl diphosphate synthase 1; Fdps farnesyl diphosphate dynthase; Fdft1 farnesyl-diphosphate farnesyltransferase 1 [57]; Sqle squalene epoxidase; Lss lanosterol synthase; Cyp51 lanosterol 14-alpha-demethylase [17], Tm7sf2 C-14 sterol reductase; Lbr lamin-B receptor; Sc4mol methylsterol monooxygenase 1*(WTSI); Nsdhl NAD(P) dependent steroid dehydrogenase-like [58], [59]; Hsd17b7 hydroxysteroid (17-beta) dehydrogenase 7 [60]; Sc5d lathosterol oxidase [61]; Dhcr7 7-dehydrocholesterol reductase [62]; Ebp emopamil binding protein (sterol isomerase) [63]; Dhcr24 24-dehydrocholesterol reductase [41], [64]; Cyp7a1 cholesterol 7-alpha-monooxygenase [65], [66]; Hsd3b7 3 beta-hydroxysteroid dehydrogenase type 7 [67]; Cyp8b1 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase [68]; Cyp27a1 Sterol 26-hydroxylase [69]; Cyp7b1 25-hydroxycholesterol 7-alpha-hydroxylase [70]; Scrab1 scavenger receptor class b, member 1 [71]; Ldlr low density lipoprotein receptor [72]; Cd36 fatty acid translocase [73], [74]; Abcg5 ATP-binding cassette sub-family g member 5; Abcg8 ATP-binding cassette sub-family g member 8 [75].

Mentions: Cholesterol, an essential compound of cell membranes, regulates permeability, fluidity, and membrane signaling capacity [1], is a precursor of steroid hormones and bile acids, and plays an important role in cell proliferation [2], [3]. Cholesterol originates from two sources – the dietary intake (30–50%) and de novo synthesis (50–70% in men) [4]. Its abnormal blood concentration leads to the increased risk of heart diseases and brain strokes. Thus, regulation on the cellular level and on the level of the entire organism is essential [5]. The lipid homeostasis is performed mainly by the liver, the major organ of lipid clearance [6] and synthesis. Almost 40% of the cholesterol is synthesized in the murine liver [7], and the pathway is well conserved in mammals. The loss of function of genes from cholesterol synthesis, metabolism or transport results in lethality or other serious conditions, where the severity of the phenotype depends on the position of gene in the pathway [8], [9], [10], [11]. Most murine studies focus on the complete knockout models that are unlikely to be found in humans, due to the lethal developmental phenotype, while mice heterozygous for the cholesterol-linked genes seldom present a distinct phenotype (Figure 1). However, the cholesterol homeostasis in humans exhibits examples where abnormalities manifest with the heterozygous variants, such as in the genes of cholesterol synthesis (HMGCR, DHCR7, DHCR24 and CYP51A1), where polymorphisms associate with preterm delivery or low birth weight [12], [13], [14].


Hidden disease susceptibility and sexual dimorphism in the heterozygous knockout of Cyp51 from cholesterol synthesis.

Lewinska M, Juvan P, Perse M, Jeruc J, Kos S, Lorbek G, Urlep Z, Keber R, Horvat S, Rozman D - PLoS ONE (2014)

Characteristics of knock-out and heterozygous knock-out mouse models.Figure shows mouse characteristics in the cholesterol synthesis (A), bile acid synthesis pathways (B) and lipid transporters (C). In red are marked disease phenotypes, while in green are marked mild/no phenotype. *The heterozygous knock-out models often were not thoroughly investigated. Gene names and references to literature describing mouse models: Acat2 acetyl-coenzyme A acetyltransferase 2; Hmgcs1 3-hydroxy-3-methylglutaryl-coa synthase 1; Hmgcr 3-hydroxy-3-methylglutaryl-coa reductase [55]; Pmvk phosphomevalonate kinase; Mvd diphosphomevalonate decarboxylase; Mvk mevalonate kinase [56]; Idi1 isopentenyl-diphosphate delta isomerase 1; Ggps1 geranylgeranyl diphosphate synthase 1; Fdps farnesyl diphosphate dynthase; Fdft1 farnesyl-diphosphate farnesyltransferase 1 [57]; Sqle squalene epoxidase; Lss lanosterol synthase; Cyp51 lanosterol 14-alpha-demethylase [17], Tm7sf2 C-14 sterol reductase; Lbr lamin-B receptor; Sc4mol methylsterol monooxygenase 1*(WTSI); Nsdhl NAD(P) dependent steroid dehydrogenase-like [58], [59]; Hsd17b7 hydroxysteroid (17-beta) dehydrogenase 7 [60]; Sc5d lathosterol oxidase [61]; Dhcr7 7-dehydrocholesterol reductase [62]; Ebp emopamil binding protein (sterol isomerase) [63]; Dhcr24 24-dehydrocholesterol reductase [41], [64]; Cyp7a1 cholesterol 7-alpha-monooxygenase [65], [66]; Hsd3b7 3 beta-hydroxysteroid dehydrogenase type 7 [67]; Cyp8b1 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase [68]; Cyp27a1 Sterol 26-hydroxylase [69]; Cyp7b1 25-hydroxycholesterol 7-alpha-hydroxylase [70]; Scrab1 scavenger receptor class b, member 1 [71]; Ldlr low density lipoprotein receptor [72]; Cd36 fatty acid translocase [73], [74]; Abcg5 ATP-binding cassette sub-family g member 5; Abcg8 ATP-binding cassette sub-family g member 8 [75].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231084&req=5

pone-0112787-g001: Characteristics of knock-out and heterozygous knock-out mouse models.Figure shows mouse characteristics in the cholesterol synthesis (A), bile acid synthesis pathways (B) and lipid transporters (C). In red are marked disease phenotypes, while in green are marked mild/no phenotype. *The heterozygous knock-out models often were not thoroughly investigated. Gene names and references to literature describing mouse models: Acat2 acetyl-coenzyme A acetyltransferase 2; Hmgcs1 3-hydroxy-3-methylglutaryl-coa synthase 1; Hmgcr 3-hydroxy-3-methylglutaryl-coa reductase [55]; Pmvk phosphomevalonate kinase; Mvd diphosphomevalonate decarboxylase; Mvk mevalonate kinase [56]; Idi1 isopentenyl-diphosphate delta isomerase 1; Ggps1 geranylgeranyl diphosphate synthase 1; Fdps farnesyl diphosphate dynthase; Fdft1 farnesyl-diphosphate farnesyltransferase 1 [57]; Sqle squalene epoxidase; Lss lanosterol synthase; Cyp51 lanosterol 14-alpha-demethylase [17], Tm7sf2 C-14 sterol reductase; Lbr lamin-B receptor; Sc4mol methylsterol monooxygenase 1*(WTSI); Nsdhl NAD(P) dependent steroid dehydrogenase-like [58], [59]; Hsd17b7 hydroxysteroid (17-beta) dehydrogenase 7 [60]; Sc5d lathosterol oxidase [61]; Dhcr7 7-dehydrocholesterol reductase [62]; Ebp emopamil binding protein (sterol isomerase) [63]; Dhcr24 24-dehydrocholesterol reductase [41], [64]; Cyp7a1 cholesterol 7-alpha-monooxygenase [65], [66]; Hsd3b7 3 beta-hydroxysteroid dehydrogenase type 7 [67]; Cyp8b1 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase [68]; Cyp27a1 Sterol 26-hydroxylase [69]; Cyp7b1 25-hydroxycholesterol 7-alpha-hydroxylase [70]; Scrab1 scavenger receptor class b, member 1 [71]; Ldlr low density lipoprotein receptor [72]; Cd36 fatty acid translocase [73], [74]; Abcg5 ATP-binding cassette sub-family g member 5; Abcg8 ATP-binding cassette sub-family g member 8 [75].
Mentions: Cholesterol, an essential compound of cell membranes, regulates permeability, fluidity, and membrane signaling capacity [1], is a precursor of steroid hormones and bile acids, and plays an important role in cell proliferation [2], [3]. Cholesterol originates from two sources – the dietary intake (30–50%) and de novo synthesis (50–70% in men) [4]. Its abnormal blood concentration leads to the increased risk of heart diseases and brain strokes. Thus, regulation on the cellular level and on the level of the entire organism is essential [5]. The lipid homeostasis is performed mainly by the liver, the major organ of lipid clearance [6] and synthesis. Almost 40% of the cholesterol is synthesized in the murine liver [7], and the pathway is well conserved in mammals. The loss of function of genes from cholesterol synthesis, metabolism or transport results in lethality or other serious conditions, where the severity of the phenotype depends on the position of gene in the pathway [8], [9], [10], [11]. Most murine studies focus on the complete knockout models that are unlikely to be found in humans, due to the lethal developmental phenotype, while mice heterozygous for the cholesterol-linked genes seldom present a distinct phenotype (Figure 1). However, the cholesterol homeostasis in humans exhibits examples where abnormalities manifest with the heterozygous variants, such as in the genes of cholesterol synthesis (HMGCR, DHCR7, DHCR24 and CYP51A1), where polymorphisms associate with preterm delivery or low birth weight [12], [13], [14].

Bottom Line: Cyp51+/- females fed high-fat, high-cholesterol diet were leaner and had elevated plasma corticosterone compared to controls.The Cyp51+/- females had a modified lipid storage homeostasis protecting them from weight-gain when fed high-fat high-cholesterol diet.Malfunction of one Cyp51 allele therefore initiates disease pathways towards cholesterol-linked liver pathologies and sex-dependent response to dietary challenge.

View Article: PubMed Central - PubMed

Affiliation: Center for Functional Genomics and Bio-Chips, Faculty of Medicine, University of Ljubljana, SI-1000, Ljubljana, Slovenia.

ABSTRACT
We examined the genotype-phenotype interactions of Cyp51+/- mice carrying one functional allele of lanosterol 14α-demethylase from cholesterol biosynthesis. No distinct developmental or morphological abnormalities were observed by routine visual inspection of Cyp51+/- and Cyp51+/+ mice and fertility was similar. We further collected a large data-set from female and male Cyp51+/- mice and controls fed for 16 weeks with three diets and applied linear regression modeling. We used 3 predictor variables (genotype, sex, diet), and 39 response variables corresponding to the organ characteristics (7), plasma parameters (7), and hepatic gene expression (25). We observed significant differences between Cyp51+/- and wild-type mice in organ characteristics and blood lipid profile. Hepatomegaly was observed in Cyp51+/- males, together with elevated total and low-density lipoprotein cholesterol. Cyp51+/- females fed high-fat, high-cholesterol diet were leaner and had elevated plasma corticosterone compared to controls. We observed elevated hepatocyte apoptosis, mitosis and lipid infiltration in heterozygous knockouts of both sexes. The Cyp51+/- females had a modified lipid storage homeostasis protecting them from weight-gain when fed high-fat high-cholesterol diet. Malfunction of one Cyp51 allele therefore initiates disease pathways towards cholesterol-linked liver pathologies and sex-dependent response to dietary challenge.

Show MeSH
Related in: MedlinePlus