TY - JOUR
T1 - Ursodeoxycholic Acid for Trans Intestinal Cholesterol Excretion Stimulation
T2 - A Randomized Placebo Controlled Crossover Study
AU - Oostveen, Reindert F.
AU - Kaiser, Yannick
AU - Hartgers, Merel L.
AU - Meessen, Emma C.E.
AU - Grefhorst, Aldo
AU - Hovingh, G. Kees
AU - Kuipers, Folkert
AU - Stroes, Erik S.G.
AU - Groen, Albert K.
AU - Reeskamp, Laurens F.
N1 - Publisher Copyright:
© 2024 The Author(s).
PY - 2024/10/15
Y1 - 2024/10/15
N2 - BACKGROUND: The trans intestinal cholesterol excretion (TICE) pathway is a potential therapeutic target to reduce plasma low-density lipoprotein (LDL) cholesterol levels. TICE encompasses the direct excretion of cholesterol by enterocytes into feces. In mice, TICE has been shown to be stimulated by a hydrophilic bile acid pool, resulting in increased fecal neutral sterol loss and reduced plasma cholesterol levels. We investigated whether treatment with a hydrophilic bile acid, ursodeoxycholic acid (UDCA), would increase fecal neutral sterols in humans as a proxy for TICE.METHODS AND RESULTS: We performed a randomized, double-blind, placebo-controlled, cross-over trial in 20 male partici-pants aged >18 years, with plasma LDL cholesterol levels ≥2.6 mmol/L. After a run-in period of ezetimibe 20 mg once daily for 3 weeks, patients were randomized to UDCA 600 mg or placebo orally once daily for 2 weeks. After a 3 week washout, patients underwent the alternate treatment. At baseline, mean (SD) age, body mass index, and plasma LDL cholesterol were 59±11.3 years, 26.4±3.1 kg/m2, and 3.9±0.8 mmol/L, respectively. After UDCA treatment, the plasma bile acid hydrophobic-ity index was reduced compared with placebo (−118.7% versus +2.3%, P<0.001). The fecal neutral sterols did not change (−5.8% versus +18.8%, P=0.51) and treatment with UDCA increased LDL cholesterol with 0.39 mmol/L (+8.1% versus −3.64%, P=0.002) when compared with placebo.CONCLUSIONS: UDCA in combination with ezetimibe increased plasma bile acid hydrophilicity in healthy subjects with LDL cholesterol levels >2.6 mmol/L but did not result in increased fecal neutral sterols or decreased LDL cholesterol. This suggests that TICE is not stimulated by an increase in the hydrophilicity of the bile acid pool in humans.
AB - BACKGROUND: The trans intestinal cholesterol excretion (TICE) pathway is a potential therapeutic target to reduce plasma low-density lipoprotein (LDL) cholesterol levels. TICE encompasses the direct excretion of cholesterol by enterocytes into feces. In mice, TICE has been shown to be stimulated by a hydrophilic bile acid pool, resulting in increased fecal neutral sterol loss and reduced plasma cholesterol levels. We investigated whether treatment with a hydrophilic bile acid, ursodeoxycholic acid (UDCA), would increase fecal neutral sterols in humans as a proxy for TICE.METHODS AND RESULTS: We performed a randomized, double-blind, placebo-controlled, cross-over trial in 20 male partici-pants aged >18 years, with plasma LDL cholesterol levels ≥2.6 mmol/L. After a run-in period of ezetimibe 20 mg once daily for 3 weeks, patients were randomized to UDCA 600 mg or placebo orally once daily for 2 weeks. After a 3 week washout, patients underwent the alternate treatment. At baseline, mean (SD) age, body mass index, and plasma LDL cholesterol were 59±11.3 years, 26.4±3.1 kg/m2, and 3.9±0.8 mmol/L, respectively. After UDCA treatment, the plasma bile acid hydrophobic-ity index was reduced compared with placebo (−118.7% versus +2.3%, P<0.001). The fecal neutral sterols did not change (−5.8% versus +18.8%, P=0.51) and treatment with UDCA increased LDL cholesterol with 0.39 mmol/L (+8.1% versus −3.64%, P=0.002) when compared with placebo.CONCLUSIONS: UDCA in combination with ezetimibe increased plasma bile acid hydrophilicity in healthy subjects with LDL cholesterol levels >2.6 mmol/L but did not result in increased fecal neutral sterols or decreased LDL cholesterol. This suggests that TICE is not stimulated by an increase in the hydrophilicity of the bile acid pool in humans.
KW - ezetimibe
KW - lipids
KW - trans intestinal cholesterol excretion
KW - ursodeoxycholic acid
UR - http://www.scopus.com/inward/record.url?scp=85206598436&partnerID=8YFLogxK
U2 - 10.1161/JAHA.124.035259
DO - 10.1161/JAHA.124.035259
M3 - Article
C2 - 39377212
AN - SCOPUS:85206598436
SN - 2047-9980
VL - 13
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 20
M1 - e035259
ER -