CDK12 is a kinase associated with elongating RNA polymerase II (RNAPII) and is frequently mutated in cancer. CDK12 depletion reduces the expression of homologous recombination (HR) DNA repair genes, but comprehensive insight into its target genes and cellular processes is lacking. We use a chemical genetic approach to inhibit analog‐sensitive CDK12, and find that CDK12 kinase activity is required for transcription of core DNA replication genes and thus for G1/S progression. RNA‐seq and ChIP‐seq reveal that CDK12 inhibition triggers an RNAPII processivity defect characterized by a loss of mapped reads from 3′ends of predominantly long, poly(A)‐signal‐rich genes. CDK12 inhibition does not globally reduce levels of RNAPII‐Ser2 phosphorylation. However, individual CDK12‐dependent genes show a shift of P‐Ser2 peaks into the gene body approximately to the positions where RNAPII occupancy and transcription were lost. Thus, CDK12 catalytic activity represents a novel link between regulation of transcription and cell cycle progression. We propose that DNA replication and HR DNA repair defects as a consequence of CDK12 inactivation underlie the genome instability phenotype observed in many cancers.

J. Neurochem. (2011) 119, 1016–1028. Abstract Currently, little is known about the role of intracellular triacylglycerol (TAG) lipases in the brain. Adipose triglyceride lipase (ATGL) is encoded by the PNPLA2 gene and catalyzes the rate‐limiting step of lipolysis. In this study, we investigated the effects of ATGL deficiency on brain lipid metabolism in vivo using an established knock‐out mouse model (ATGL‐ko). A moderate decrease in TAG hydrolase activity detected in ATGL‐ko versus wild‐type brain tissue was accompanied by a 14‐fold increase in TAG levels and an altered composition of TAG‐associated fatty acids in ATGL‐ko brains. Oil Red O staining revealed a severe accumulation of neutral lipids associated to cerebrovascular cells and in distinct brain regions namely the ependymal cell layer and the choroid plexus along the ventricular system. In situ hybridization histochemistry identified ATGL mRNA expression in ependymal cells, the choroid plexus, pyramidal cells of the hippocampus, and the dentate gyrus. Our findings imply that ATGL is involved in brain fatty acid metabolism, particularly in regions mediating transport and exchange processes: the brain–CSF interface, the blood–CSF barrier, and the blood–brain barrier.

Elevated pancreatic β-cell cholesterol levels impair insulin secretion and reduce plasma insulin levels. This study establishes that low plasma insulin levels have a detrimental effect on two major insulin target tissues: adipose tissue and skeletal muscle. Mice with increased β-cell cholesterol levels were generated by conditional deletion of the ATP-binding cassette transporters, ABCA1 and ABCG1, in β-cells (β-DKO mice). Insulin secretion was impaired in these mice under basal and high-glucose conditions, and glucose disposal was shifted from skeletal muscle to adipose tissue. The β-DKO mice also had increased body fat and adipose tissue macrophage content, elevated plasma interleukin-6 and MCP-1 levels, and decreased skeletal muscle mass. They were not, however, insulin resistant. The adipose tissue expansion and reduced skeletal muscle mass, but not the systemic inflammation or increased adipose tissue macrophage content, were reversed when plasma insulin levels were normalized by insulin supplementation. These studies identify a mechanism by which perturbation of β-cell cholesterol homeostasis and impaired insulin secretion increase adiposity, reduce skeletal muscle mass, and cause systemic inflammation. They further identify β-cell dysfunction as a potential therapeutic target in people at increased risk of developing type 2 diabetes.

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Click here to view linked References HIGHLIGHTS 1) Asx exerts beneficial effects similar to Bex in brain capillary endothelial cells 2) non-amyloidogenic APP processing is enhanced via BACE1 and ADAM10 modulation 3) ABCA1 is upregulated and cellular cholesterol efflux is stimulated involving nuclear receptor-dependent mechanisms 4) LRP-1 is up regulated along with augmented Aβ uptake/transcytosis 5) Silencing of LRP-1 or inhibition of ABCA1 reverses effects of Asx and Bex on APP processing/Aß species 6) Asx and Bex considerably reduce cerebral and cerebrovascular Aβ load in vivo in 3xTg

Background: Liver X receptor activation promotes formation of HDL-like particles at the blood-brain barrier (BBB). Results: Cerebrovascular endothelial cells express phospholipid transfer protein (PLTP) that transfers phospholipids, remodels HDL, and supports cellular cholesterol efflux. Conclusion: PLTP is involved in HDL genesis and remodeling at the BBB. Significance: We demonstrate a direct role of PLTP in HDL metabolism at the blood-brain interface.

PLTP mediates PL transfer and participates in reverse cholesterol transport pathways at the fetoplacental barrier. Enhanced cellular cholesterol efflux from HPEC to fetal HDL remodeled by PLTP supports the idea of a local atheroprotective role of PLTP in the placental vasculature.

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