Figure 1.
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].
Figure 2.
The expression of Cyp51 (A) on mRNA and (B) protein levels (western blot analysis).
Figure 3.
The global effect of Cyp51 haploinsufficiency.
The genotype effect shown on blood lipid profile (n = 8–15) and hepatic gene expression analyses in Cyp51+/− mice compared to Cyp51+/+ matched with sex (n = 4–7) and blood lipid profile differences. The direction of arrows indicate (↑) up-regulation or (↓) down-regulation of expression in heterozygous females (♀) and males (♂). The direction of arrows shows also a trend of change in genes that did not reach statistical significance. *(p<0.1); **(p<0.05). Results are joined for all diets.
Table 1.
Significant differences in gross phenotype between Cyp51+/− and Cyp51+/+ mice.
Figure 4.
Liver histology, hematoxylin and eosin stain.
A Mitotic (left) and apoptotic cells with hyper-eosinophilic cytoplasm containing fragments of dense basophilic nuclear material (right) in Cyp51+/− mice on LFnC diet; original magnification x400. B Mild focal steatosis in Cyp51+/+ mice and moderate steatosis in Cyp51+/− mice on HFnC and HFC diets; original magnification x100.
Table 2.
Summary of the liver histology.
Table 3.
Significant differences between Cyp51+/− and Cyp51+/+ mice on each diet separately.
Figure 5.
The diet-genotype interactions (effect of high fat feeding).
Plots showing the change in expression levels in males and females, both Cyp51+/− (red) and Cyp51+/+ (blue). Grey color indicates a linear smooth of 0.95 confidence intervals. The significant interactions between factors (Cyp51 genotype and diet) that can be understood as the differences between slopes of lines are indicated by their p values.