Co‐segregation of Soat1 mutations with non‐HDL cholesterol, body weight, and atherosclerosis in inbred mouse strains

Sterol o‐acyltransferase 1 (Soat1, also known as ACAT1) is an endoplasmic reticulum enzyme that catalyzes free cholesterol to cholesterol ester. We identified four single‐nucleotide polymorphisms (SNPs) (A421C, A439G, C454T, and C613T) within the coding region of Soat1 between mouse strains C57BL/6 (B6) and C3H and two of the SNPs led to amino‐acid substitutions (Ile147Val and His205Tyr). We then sequenced the coding region of Soat1 in 33 additional mouse strains and found three Soat1 protein variants, including 147Ile 205His, 147Val205His, and 147Val205Tyr. When fed a high fat/cholesterol diet with cholate for 8 weeks, mouse strains with the 147Val205His variant had significantly higher non‐HDL levels (343 ± 161 vs. 140 ± 43 or 129 ± 70, P = 9.9E‐05 in female; 331 ± 240 vs. 127 ± 47 or 122 ± 93; P = 0.0039 in male), smaller body weight (13 ± 1 vs. 23 ± 5 or 26 ± 5, P = 0.0009 in female; 15 ± 1 vs. 28 ± 6 or 30 ± 4; P = 0.0002 in male), and were absent in aortic fatty streak lesions (0 vs. 343 ± 501 or 259 ± 690 in female P =0.65; and 553 ± 961 or 287 ± 1036 in male; P =0.58 ). Thus, these results support Soat1 to be an important gene contributing to hyperlipidemia, body weight, and atherosclerosis in mice.