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LXR-dependent regulation of macrophage-specific reverse cholesterol transport is impaired in a model of genetic diabesity
- Source :
- Translational research : the journal of laboratory and clinical medicine. 186
- Publication Year :
- 2017
-
Abstract
- Diabesity and fatty liver have been associated with low levels of high-density lipoprotein cholesterol, and thus could impair macrophage-specific reverse cholesterol transport (m-RCT). Liver X receptor (LXR) plays a critical role in m-RCT. Abcg5/g8 sterol transporters, which are involved in cholesterol trafficking into bile, as well as other LXR targets, could be compromised in the livers of obese individuals. We aimed to determine m-RCT dynamics in a mouse model of diabesity, the db/db mice. These obese mice displayed a significant retention of macrophage-derived cholesterol in the liver and reduced fecal cholesterol elimination compared with nonobese mice. This was associated with a significant downregulation of the hepatic LXR targets, including Abcg5/g8. Pharmacologic induction of LXR promoted the delivery of total tracer output into feces in db/db mice, partly due to increased liver and small intestine Abcg5/Abcg8 gene expression. Notably, a favorable upregulation of the hepatic levels of ABCG5/G8 and NR1H3 was also observed postoperatively in morbidly obese patients, suggesting a similar LXR impairment in these patients. In conclusion, our data show that downregulation of the LXR axis impairs cholesterol transfer from macrophages to feces in db/db mice, whereas the induction of the LXR axis partly restores impaired m-RCT by elevating the liver and small intestine expressions of Abcg5/g8.
- Subjects :
- 0301 basic medicine
Male
medicine.medical_specialty
Lipoproteins
ABCG8
03 medical and health sciences
chemistry.chemical_compound
Diabetes mellitus genetics
Mice
Downregulation and upregulation
Physiology (medical)
Internal medicine
medicine
Diabetes Mellitus
Animals
Obesity
ATP Binding Cassette Transporter, Subfamily G, Member 5
Liver X receptor
Liver X Receptors
biology
Cholesterol
Macrophages
Biochemistry (medical)
Fatty liver
Reverse cholesterol transport
ATP Binding Cassette Transporter, Subfamily G, Member 8
Public Health, Environmental and Occupational Health
Biological Transport
General Medicine
medicine.disease
Up-Regulation
030104 developmental biology
Endocrinology
chemistry
ABCG5
biology.protein
lipids (amino acids, peptides, and proteins)
Signal Transduction
Subjects
Details
- ISSN :
- 18781810
- Volume :
- 186
- Database :
- OpenAIRE
- Journal :
- Translational research : the journal of laboratory and clinical medicine
- Accession number :
- edsair.doi.dedup.....cbf9817a70ad73a13dfe04dff1b550d8