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NPC1L1 and ABCG5/8 induction explain synergistic fecal cholesterol excretion in ob/ob mice co-treated with PPAR-α and LXR agonists.
- Source :
-
Molecular and cellular biochemistry [Mol Cell Biochem] 2020 Oct; Vol. 473 (1-2), pp. 247-262. Date of Electronic Publication: 2020 Jul 13. - Publication Year :
- 2020
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Abstract
- Reverse cholesterol transport (RCT) and transintestinal cholesterol efflux (TICE) are two important pathways for body cholesterol elimination. We studied these pathways in an animal model of diabetes and obesity (ob/ob) where HDL function is compromised as a result of hyperglycemia, low-grade inflammation and oxidative stress. Co-treatment of ob/ob mice with PPAR-α (fenofibrate) and LXR (T0901317) agonists increased fecal cholesterol by 12-fold; PPAR-α and LXR agonists individually showed 2.6- and 4.0-fold fecal cholesterol excretion, respectively. We investigated the mechanism of synergistic efficacy of PPAR-α and LXR agonists in fecal cholesterol excretion. LXR agonist and the combination of PPAR-α and LXR agonists had greater HDL-C elevation. Ex vivo cholesterol efflux showed correlation with the fecal cholesterol excretion but was not sufficient to explain 12-fold increases in the fecal cholesterol in the co-treated mice. Therefore, we examined TICE to explain the 12-fold increases in the fecal cholesterol. A strong positive correlation of fecal cholesterol with ATP binding cassette transporter G5 (ABCG5) and G8 and a negative correlation with NPC1L1 was observed. ABCG5, G8 and NPC1L1 are involved in intestinal cholesterol absorption. The extent of influence of PPAR-α and LXR agonists on RCT and TICE was distinctly different. PPAR-α agonist increased fecal cholesterol primarily by influencing TICE, while LXR agonist influenced fecal cholesterol excretion via both RCT and TICE mechanisms. Synergistic efficacy on fecal cholesterol excretion following co-treatment with PPAR-α and LXR agonists occurred through a combination of RCT, TICE, and the key enzyme in bile synthesis, cholesterol 7-α hydroxylase (cyp7a1). These results suggest that cholesterol efflux, biliary cholesterol excretion, and TICE collectively contributed to the 12-fold increases in the fecal cholesterol excretion in ob/ob mice co-treated with PPAR-α and LXR agonists.
- Subjects :
- Animals
Drug Synergism
Fenofibrate agonists
Hydrocarbons, Fluorinated agonists
Male
Mice
Mice, Obese
Sulfonamides agonists
ATP Binding Cassette Transporter, Subfamily G, Member 5 metabolism
ATP Binding Cassette Transporter, Subfamily G, Member 8 metabolism
Cholesterol metabolism
Feces
Fenofibrate pharmacology
Hydrocarbons, Fluorinated pharmacology
Lipoproteins metabolism
Liver X Receptors agonists
Liver X Receptors metabolism
Membrane Transport Proteins metabolism
PPAR alpha agonists
PPAR alpha metabolism
Sulfonamides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1573-4919
- Volume :
- 473
- Issue :
- 1-2
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32661772
- Full Text :
- https://doi.org/10.1007/s11010-020-03826-3