Experiment
A previously identified locus for plasma plant sterol levels, Plast1, was further examined using congenic line analysis. Plast1 mappped to 17 cM on mouse Chromosome 14 with a QTL interval spanning 5 cM - 40 cM. A congenic line named 14KK was constructed by introgression of CASA/Rk-derived chromosome 14 DNA from 4 cM - 60 cM onto a C57BL/6J genetic background. Congenic line 14KK was then used to create two non-overlapping subcongenic lines named 14PKK and 14DKK. Donor strain CASA/Rk displays decreased plasma plant sterol levels compared to background strain C57BL/6J. Animals were phenotyped at 11 weeks of age.
14KK (full congenic) males displayed significantly decreased plasma campesterol, sitosterol, stigmasterol, and brassicasterol levels compared to C57BL/6J controls. However, plasma plant sterol levels in 14KK females did not differ from controls. This finding reaffirms the presence of Plast1 on chromosome 14 and revealsa sex-dependent effect. Cholesterol absorption rate, but not food intake, was significantly lower in 14KK males compared to C57BL/6J males. Therefore, the effect of Plast1 in decreasing plasma plant sterol levels in males is likely explained by decreasedcholesterol absorption.
14PKK male and female mice (subcongenic for CASA-Rk DNA between D14Mit251 [4 cM] and D14Mit233 [19.5 cM]) displayed significantly decreased plasma plant sterol levels and decreased cholesterol absorption compared to C57BL/6J controls. Subcongenic 14PKK male and female animals also display increased biliary sterol secretion and elevated bile-to-plasma plant sterol ratios compared to controls. Food consumption did not differ between 14PKK and C57BL/6J.
14DKK male and female mice (subcongenic for CASA/Rk DNA between D14Mit259 [19.5 cM] and D14Mit267 [60 cM]) displayed significantly decreased plasma plant sterol levels and decreased cholesterol absorption compared to C57BL/6J controls. Food consumption did not differ between 14DKK and C57BL/6J. However, female 14DKK mice have decreased absolute biliary plant sterol concentrations and bile-to-plasma plant sterol concentration ratios compared to C57BL/7J females.
Authors conclude that at least 2 loci are involved in the Plast1 locus. The proximal portion of the locus (Plast1a) may harbor a gene involved in both decreasing intestinal sterol absorption and increasing biliary sterol secretion. The distal portion of the locus (Plast1b) appears to be involved in decreasing sterol absorption. Other gene-gene effects in the Plast1a-Plast1b interval may explain the sex-dependent effects present in 14KK congenics but not observed in 14PKK or 14DKK subcongenics.