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Lack of responsiveness to plant sterols in wild type C57BL/6J mice is due to increased HMG‐CoA reductase transcription and higher fractional cholesterol synthesis rate

Although plant sterols (PS) are effective in reducing plasma cholesterol (C) in humans and various animal models, previous work suggests that wild type C57BL/6J mice do not respond to PS therapy despite reductions in intestinal cholesterol absorption. To explain this non‐responsiveness, we examined changes in hepatic HMG‐CoA reductase (HMG‐CoAr) expression and C synthesis in C57BL/6J mice. Mice (n = 10) were fed a high‐fat control diet or the control diet with 2% PS for 30 d in a randomized block design. Mice received an intraperitoneal injection of deuterium oxide 2h prior to sacrifice and whole‐body C synthesis was measured by deuterium incorporation. Although total C and non‐HDL C did not differ between treatments, PS consumption reduced (P<0.05) plasma triglycerides by 29% compared to control (0.68±0.02 vs. 0.91±0.17 mmol/L). PS consumption increased hepatic HMG‐CoAr mRNA expression (2.7 fold of control, P<0.05) but did not affect (P>0.05) HMG‐CoAr protein abundance. In agreement with HMG‐CoAr mRNA expression, PS consumption increased whole‐body fractional C synthesis rate compared to control (2.0±0.16 vs. 1.3±0.43 % day−1). HMG‐CoAr mRNA expression was positively correlated with whole‐body C synthesis (r = 0.61, P<0.05). The lack of response of plasma C to PS consumption in C57BL/6J mice is due to an upregulation of hepatic HMG‐CoAr mRNA expression and a compensatory increase in C synthesis. Funded by NSERC.