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Effects of physical activity on the gallbladder and biliary tract in health and disease
Published in Roy J. Shephard, Physical Activity and the Abdominal Viscera, 2017
Studies in mice bred for their susceptibility to gallbladder disease have shown that training also increases the hepatic expression of two genes (LDLr and SRB1) that are known to be involved in the clearance of cholesterol. Exercised mice demonstrate an up-regulation of the protein Cyp27 that is associated with the hepatic production of bile acids.[83] The net effect of exercise upon the intestinal reabsorption of cholesterol remains less clear. Trained animals show a reduced expression of NPC1L1 (which would reduce cholesterol reabsorption), but at the same time there is a reduction in the expression of ABCG5 and G8 (which would have the effect of increasing cholesterol resorption).[83]
Gallbladder Disease
Published in John F. Pohl, Christopher Jolley, Daniel Gelfond, Pediatric Gastroenterology, 2014
Cholesterol is secreted into the biliary canaliculus by the transporter proteins ABCG5 and G8. As a highly insoluble product, cholesterol is kept in solution by the formation of micelles with bile salts and phospholipid. Again, with increasing solute concentration in the gallbladder this process may be tipped into crystalization and cholesterol stone formation. This sequence is much more multilayered than is the case for pigment stones, and the interplay of underlying factors is complex. Obesity, a family history of gallbladder disease, and the female gender predispose to stone formation in the pediatric age-group as for adults. Most patients become symptomatic during adolescence.
Treatment of Vulnerable Plaques: Current and Future Strategies
Published in Levon Michael Khachigian, High-Risk Atherosclerotic Plaques, 2004
Leonard Kritharides, David Brieger, S. Benedict Freedman, Harry C. Lowe
Clearance of cholesterol from LDL and HDL by the liver is relevant to this process and involves the selective uptake of cholesteryl ester by SRB-1180 and the excretion of biliary sterols by the expression of ABCG5 and ABCG8.181 SRB-1 is also likely to play a role in facilitating cholesterol mobilization from peripheral stores.182 Although over-expression of SRB-1 lowers plasma HDLc, its role in mediating net clearance of cholesterol from tissues is supported by accelerated atherosclerosis with cardiac ischemia in mice deficient in SRB-1.183 Because several key components of the reverse cholesterol transport pathway are regulated by ligands for LXR and RXR, these may be suitable targets for future therapies, and there is some indication they can be modulated by PPAR ligands.
What can we learn from the platelet lipidome?
Published in Platelets, 2023
Gaëtan Chicanne, Jean Darcourt, Justine Bertrand-Michel, Cédric Garcia, Agnès Ribes, Bernard Payrastre
However, whether specific platelet lipidomic profiles may become diseases signature remains to be established. Moreover, how altered platelet lipidome can be involved in platelet-dependent pathologies is still poorly understood. Yet, some inherited pathologies are directly linked to platelet lipid modifications. This includes the loss of PS exposure due to TMEM16F scramblase mutations impairing the procoagulant function of platelets in the bleeding Scott syndrome [32], the rare inherited cPLA2 deficiency leading to platelet dysfunction [21], the decreased expression of PLCβ2 linked to hypo-responsive platelets [33], or the loss of function of the PI(4,5)P2 5-phosphatase affecting platelet responses in the LOWE syndrome [34]. Some mouse models have also pointed to new important lipid-related pathways that should stimulate to prioritize a lipidomic analysis in patients. For instance, as mentioned above, mice lacking sphingomyelin phosphodiesterase 1 have platelet dysfunction suggesting that human platelets deficient in this enzyme, such as platelets from Niemann-Pick patients, may be affected. A mouse model of sitosterolemia caused by a mutation in the ABCG5 or ABCG8 transporter genes has linked the accumulation of free plant sterols in platelet membranes to dysregulation of platelet functions leading to macrothrombocytopenia and bleeding [35]. Lipidomic studies on platelets from sitosterolemia patients should bring interesting information as well as potential diagnostic and disease monitoring markers.
Beyond the Usual Suspects: Expanding on Mutations and Detection for Familial Hypercholesterolemia
Published in Expert Review of Molecular Diagnostics, 2021
Shirin Ibrahim, Joep C. Defesche, John J.P. Kastelein
Variants in the genes encoding adenosine triphosphate-binding cassette transporters G5 and G8 (ABCG5 and ABCG8) have also been shown to affect LDL-C levels. ABCG5 and ABCG8 form a heterodimer that is responsible for the transmembrane transport of sterols, in particular, plant sterols [41]. In the intestine, the complex is involved in the transport of sterols from the enterocyte into the intestinal lumen, whereas in the liver it promotes the transport of sterols into the bile. Mutations in ABCG5 and ABCG8 can cause sitosterolemia, an autosomal recessive disorder whereby plant sterols accumulate in blood and tissues. Studies have shown an association between hypercholesterolemia and sitosterolemia in the general population [41]. With the expansion of NGS panels in FH patients, variants in ABCG5 and ABCG8 have been frequently discovered. Patients with sitosterolemia can present with xanthomas and premature CAD, characteristics that closely mimic the clinical FH phenotype [56]. Studies by Tada et al. and Nomura et al. suggest that heterozygous pathogenic variants in the ABCG5/ABCG8 can worsen the clinical expression of FH in terms of additional elevation of LDL-C levels and cardiovascular risk [57,58]. Recently, we have also addressed this issue and could not confirm these findings [41].
ABCG5 and ABCG8 gene variations associated with sitosterolemia and platelet dysfunction
Published in Platelets, 2021
Jose María Bastida, Rocío Benito, José Ramón González-Porras, José Rivera
The sitosterolemia disease locus comprises two highly homologous genes, ABCG5 (Ensemble: ENSG00000138075, 26.3 Kb, 13 exons) and ABCG8 (ENSG00000143921, 39,5 kB, 13 exons) [26]. Both genes mapped at chromosome 2p21 and probably evolved from a common ancestral gene, by a tandem duplication and inversion event. Their proximity and opposite orientation suggest that these genes share a common, bidirectional promoter and regulatory elements, identified within the small (<160 bases) intergenic region that contains no conserved TATA motif(s) [26,27]. Elements thought to play a prominent role in ABCG5/ABCG8 transcriptional regulation and tissue-specific expression, by complex mechanisms not fully elucidated, includes Hepatocyte Nuclear Factor 4 alpha (HNF4α), GATA4, GATA6, Liver receptor homolog-1 (LRH-1) and Farnesoid X Receptor (FXR), two liver X receptor (LXRα and LXRβ) response elements and Forkhead Box Protein O1 (FOXO1). Moreover, both ABCG5 and ABCG8 are glycosylated, require the action of calnexin and calreticulin chaperones proteins for folding and dimerization to exit the endoplasmic reticulum. The mechanisms regulating that regulate the cell trafficking and activity of the ABCG5/G8 transporter are not well known and may implicate bile acids, sterols, and cAMP signaling. Not all the ABCG5/G8 protein appears to reside at the cell surface but intercellular pool exists that may be mobilized to promote cholesterol secretion [26–29].