Physiologically regulated transgenic ABCA1 does not reduce amyloid burden or amyloid‐beta peptide levels in vivo

J Lipid Res. 2007 Apr;48(4):914-23. Epub 2007 Jan 18. Physiologically regulated transgenic ABCA1 does not reduce amyloid burden or amyloid-beta peptide levels in vivo. Hirsch-Reinshagen V, Chan JY, Wilkinson A, Tanaka T, Fan J, Ou G, Maia LF, Singaraja RR, Hayden MR, Wellington CL. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada. Abstract ABCA1-deficient mice have low levels of poorly lipidated apolipoprotein E (apoE) and exhibit increased amyloid load. To test whether excess ABCA1 protects from amyloid deposition, we crossed APP/PS1 mice to ABCA1 bacterial artificial chromosome (BAC) transgenic mice. Compared with wild-type animals, the ABCA1 BAC led to a 50% increase in cortical ABCA1 protein and a 15% increase in apoE abundance, demonstrating that this BAC supports modest ABCA1 overexpression in brain. However, this was observed only in animals that do not deposit amyloid. Comparison of ABCA1/APP/PS1 mice with APP/PS1 controls revealed no differences in levels of brain ABCA1 protein, amyloid, Abeta, or apoE, despite clear retention of ABCA1 overexpression in the livers of these animals. To further investigate ABCA1 expression in the amyloid-containing brain, we then compared ABCA1 mRNA and protein levels in young and aged cortex and cerebellum of APP/PS1 and ABCA1/APP/PS1 animals. Compared with APP/PS1 controls, aged ABCA1/APP/PS1 mice exhibited increased ABCA1 mRNA, but not protein, selectively in cortex. Additionally, ABCA1 mRNA levels were not increased before amyloid deposition but were induced only in the presence of extensive Abeta and amyloid levels. These data suggest that an induction of ABCA1 expression may be associated with late-stage Alzheimer's neuropathology. PMID: 17235115 [PubMed - indexed for MEDLINE

Loss of Cyp8b1 improves glucose homeostasis by increasing GLP-1

10.2337/db14-0716Diabetes6441168-117

Cholesterol biosynthesis pathway is disturbed in YAC128 mice and is modulated by huntingtin mutation

Our recent analyses of the cholesterol biosynthetic pathway in Huntington's disease (HD) cells, in the R6/2 huntingtin-fragment mouse model of HD as well as in human tissues have provided the first evidence of altered activity of this pathway in genetically identifiable HD samples. Here we report that these changes also occur in the full-length-huntingtin YAC128 (yeast artificial chromosome) mouse model, which shows a consistent reduction in the activity or levels of multiple components of the cholesterogenic pathway. We also show that this phenotype is progressive and is specific for the brain region most affected in HD. Mice over-expressing the wild-type protein with 18 CAG (YAC18 mice) show the opposite phenotype with higher activity of the cholesterol biosynthetic pathway compared with littermate mice. Finally, we report that plasma levels of cholesterol, its precursors and its brain-derived catabolite 24-S-hydroxycholesterol in YAC mice mirror brain biosynthetic levels supporting further investigation of their potential as peripheral biomarkers in H

The palmitoyl acyltransferase HIP14 shares a high proportion of interactors with huntingtin: implications for a role in the pathogenesis of Huntington's disease

HIP14 is the most highly conserved of 23 human palmitoyl acyltransferases (PATs) that catalyze the post-translational addition of palmitate to proteins, including huntingtin (HTT). HIP14 is dysfunctional in the presence of mutant HTT (mHTT), the causative gene for Huntington disease (HD), and we hypothesize that reduced palmitoylation of HTT and other HIP14 substrates contributes to the pathogenesis of the disease. Here we describe the yeast two-hybrid (Y2H) interactors of HIP14 in the first comprehensive study of interactors of a mammalian PAT. Unexpectedly, we discovered a highly significant overlap between HIP14 interactors and 370 published interactors of HTT, four-fold greater than for control proteins (p=8 x 10(-5)). Nearly half of the 36 shared interactors are already implicated in HD, supporting a direct link between HIP14 and the disease. The HIP14 Y2H interaction set is significantly enriched for palmitoylated proteins that are candidate substrates. We confirmed that three of them, GPM6A, and the Sprouty domain containing proteins SPRED1 and SPRED3, are indeed palmitoylated by HIP14; the first enzyme known to palmitoylate these proteins. These novel substrates functions might be affected by reduced palmitoylation in HD. We also show that the vesicular cargo adapter optineurin, an established HTT-binding protein, co-immunoprecipitates with HIP14 but is not palmitoylated. mHTT leads to mislocalization of optineurin and aberrant cargo trafficking. Therefore, it is possible that optineurin regulates trafficking of HIP14 to its substrates. Taken together, our data raise the possibility that defective palmitoylation by HIP14 might be an important mechanism that contributes to the pathogenesis of HD

Segregation of LIPG, CETP, and GALNT2 mutations in Caucasian families with extremely high HDL cholesterol

10.1371/journal.pone.0037437PLoS ONE78e3743

Stem cell-derived polarized hepatocytes

10.1038/s41467-020-15337-2Nature Communications111167

Study on the saturation index of the carbonates in the groundwater using WATEQ4F, in layered coastal aquifers of Pondicherry

A study was conducted to bring out the relationship and behavior of different Saturation Index (SI) of carbonate minerals in layered coastal aquifers. Carbonates present in groundwater aids in different nature of the water like hardness, partial pressure of carbon-di-oxide (pCO2), pH and saturation index of different carbonate minerals at various temperatures. The SI of the carbonates helps us to define the thermodynamic stability of water and to find out the geochemical behavior of water. 98 groundwater samples were collected from specific aquifers (alluvium, upper Cuddalore, lower Cuddalore and Cretaceous) during Pre-Monsoon (May 2007) and Post-Monsoon (January 2008) seasons. The physicochemical parameters such as pH, EC, Ca, Mg, Na, K, Cl, HCO3, SO4 and PO4 were analyzed. Geochemical model, WATEQ4F was used to calculate the SI of different minerals. The SI was studied in relation to mHCO3 concentration, pCO2 and correlation between SI of different minerals