Abcc5 Knockout Mice Have Lower Fat Mass and Increased Levels of Circulating GLP-1.

OBJECTIVE: A previous genome-wide association study linked overexpression of an ATP-binding cassette transporter, ABCC5, in humans with a susceptibility to developing type 2 diabetes with age. Specifically, ABCC5 gene overexpression was shown to be strongly associated with increased visceral fat mass and reduced peripheral insulin sensitivity. Currently, the role of ABCC5 in diabetes and obesity is unknown. This study reports the metabolic phenotyping of a global Abcc5 knockout mouse. METHODS: A global Abcc5-/- mouse was generated by CRISPR/Cas9. Fat mass was determined by weekly EchoMRI and fat pads were dissected and weighed at week 18. Glucose homeostasis was ascertained by an oral glucose tolerance test, intraperitoneal glucose tolerance test, and intraperitoneal insulin tolerance test. Energy expenditure and locomotor activity were measured using PhenoMaster cages. Glucagon-like peptide 1 (GLP-1) levels in plasma, primary gut cell cultures, and GLUTag cells were determined by enzyme-linked immunosorbent assay. RESULTS: Abcc5-/- mice had decreased fat mass and increased plasma levels of GLP-1, and they were more insulin sensitive and more active. Recombinant overexpression of ABCC5 protein in GLUTag cells decreased GLP-1 release. CONCLUSIONS: ABCC5 protein expression levels are inversely related to fat mass and appear to play a role in the regulation of GLP-1 secretion from enteroendocrine cells

Newer Approaches to Management of Retinal Degenerative Disorders: Gene Therapy and Cell Replacement Therapy

Recent Advances in Ophthalmology 15204-228Indi

Investigation of the effects of the CFTR potentiator ivacaftor on human P-glycoprotein (ABCB1)

Abstract Ivacaftor is a potentiator of the CFTR chloride channel and is in worldwide clinical use for the chronic treatment of cystic fibrosis in patients. There is evidence that the bioavailability of ivacaftor in the body may be influenced by the multi-drug exporter P-glycoprotein. Here we have employed purified and reconstituted P-glycoprotein to study its interaction with ivacaftor as well as the ability of the drug to compete with a known transported substrate of the protein. We find that ivacaftor stimulates the ATPase activity of the purified protein and can compete with the transport of the fluorescent substrate Hoechst 33342. These findings lead us to conclude that ivacaftor is very likely an efficiently transported substrate of P-glycoprotein. Evidence for state-dependent binding of ivacaftor was obtained using a fluorescent, cysteine-reactive reporter dye. The quiescent, nucleotide-free state in the P-glycoprotein transport cycle appears to bind ivacaftor strongly

cGMP-grade human iPSC-derived retinal photoreceptor precursor cells rescue cone photoreceptor damage in non-human primates

10.1186/s13287-021-02539-8STEM CELL RESEARCH & THERAPY121CompletedComplete