Impaired adipose tissue insulin signalling is a critical feature of insulin resistance. Here we identify a pathway linking the lipolytic enzyme hormone-sensitive lipase (HSL) to insulin action via the glucose-responsive transcription factor ChREBP and its target, the fatty acid elongase ELOVL6. Genetic inhibition of HSL in human adipocytes and mouse adipose tissue results in enhanced insulin sensitivity and induction of ELOVL6. ELOVL6 promotes an increase in phospholipid oleic acid, which modifies plasma membrane fluidity and enhances insulin signalling. HSL deficiency-mediated effects are suppressed by gene silencing of ChREBP and ELOVL6. Mechanistically, physical interaction between HSL, independent of lipase activity, and the isoform activated by glucose metabolism ChREBPalpha impairs ChREBPalpha translocation into the nucleus and induction of ChREBPbeta, the isoform with high transcriptional activity that is strongly associated with whole-body insulin sensitivity. Targeting the HSL-ChREBP interaction may allow therapeutic strategies for the restoration of insulin sensitivity.
The kinetics of the p-nitrophenyl butyrate hydrolysis reaction, catalyzed by Candida rugosa lipase in the water-in-oil microemulsion cetyltrimethylammonium bromide/water/pentanol/hexane, was investigated. The results described in the present manuscript reveal two peculiar characteristics of the reaction: (i) the initial rate of hydrolysis is very fast and (ii) by decreasing the water content of the microemulsion, the reaction rate approaches the typical behavior of reactions performed in aqueous solution. In particular, for microemulsion systems with a high water content, the end points of the reactions are dictated by the shape stability of the microemulsion. For these systems, our methodological approach shows that the process follows a second-order kinetics equation, indicative of the dual role played by water, which is involved both as a component of the microemulsion, i.e., relevant for the microemulsion stability and as a reagent of the hydrolysis reaction. In contrast, for microemulsions containing a small amount of water, after the hydrolysis reaction the system seems to fall in the no existence range of the microemulsion. Accordingly, the kinetics results are more complex: in the initial stage, the reaction follows a zero-order kinetics equation, while for longer reaction times a first-order kinetics equation fits the experimental data, as would be expected for an enzymatic reaction in a homogeneous system. (c) 2014 American Institute of Chemical Engineers Biotechnol. Prog., 30:360-366, 2014.
Chromosome 19 has the highest gene density of all human chromosomes, more than double the genome-wide average. The large clustered gene families, corresponding high G + C content, CpG islands and density of repetitive DNA indicate a chromosome rich in biological and evolutionary significance. Here we describe 55.8 million base pairs of highly accurate finished sequence representing 99.9% of the euchromatin portion of the chromosome. Manual curation of gene loci reveals 1,461 protein-coding genes and 321 pseudogenes. Among these are genes directly implicated in mendelian disorders, including familial hypercholesterolaemia and insulin-resistant diabetes. Nearly one-quarter of these genes belong to tandemly arranged families, encompassing more than 25% of the chromosome. Comparative analyses show a fascinating picture of conservation and divergence, revealing large blocks of gene orthology with rodents, scattered regions with more recent gene family expansions and deletions, and segments of coding and non-coding conservation with the distant fish species Takifugu.
Human chromosome 16 features one of the highest levels of segmentally duplicated sequence among the human autosomes. We report here the 78,884,754 base pairs of finished chromosome 16 sequence, representing over 99.9% of its euchromatin. Manual annotation revealed 880 protein-coding genes confirmed by 1,670 aligned transcripts, 19 transfer RNA genes, 341 pseudogenes and three RNA pseudogenes. These genes include metallothionein, cadherin and iroquois gene families, as well as the disease genes for polycystic kidney disease and acute myelomonocytic leukaemia. Several large-scale structural polymorphisms spanning hundreds of kilobase pairs were identified and result in gene content differences among humans. Whereas the segmental duplications of chromosome 16 are enriched in the relatively gene-poor pericentromere of the p arm, some are involved in recent gene duplication and conversion events that are likely to have had an impact on the evolution of primates and human disease susceptibility.
Title: Effect of butanedione monoxime on the contractility of guinea pig ileum and on the electrophysiological activity of myenteric S-type neurones Lizarraga I, Alfaro MJ, Goicoechea C, Lopez F, Martin MI Ref: Neuroscience Letters, 246:105, 1998 : PubMed
2,3-Butanedione monoxime (BDM) has demonstrated protective effects on isolated cardiac tissues, and on smooth muscle but its mechanism of action is not fully understood. To simultaneously study the effect of BDM on muscle contractility and on neuronal activity, the effect of BDM was tested in the contractile force of myenteric plexus-longitudinal muscle strips and in electrophysiological activity of myenteric S-type neurones of guinea pig ileum. BDM reduces, in a dose-dependent manner, the force of the spontaneous motility and the contractions induced by acetylcholine, bethanechol and electrical stimulation. The same BDM concentrations depolarize the neuronal membrane and reduce the rate of evoked firing. The effect of BDM can be attributed to a direct effect on the smooth muscle and to modifications of the neuronal activity.
