Lean subjects with evidence of NAFLD have clinically relevant impaired glucose tolerance, low adiponectin concentrations and a distinct metabolite profile with an increased rate of PNPLA3 risk allele carriage.

PGC-1α has been implicated in the pathogenesis of neurodegenerative disorders. Several single-nucleotide polymorphisms (SNPs) located in two separate haplotype blocks of PPARGC1A have shown associations with Huntington's disease (HD) and Parkinson's disease, but causative SNPs have not been identified. One SNP (rs7665116) was located in a highly conserved 233 bp region of intron 2. To determine whether rs7665116 is located in an alternative exon, we performed 5'-RLM-RACE from exon 3 and discovered multiple new transcripts that initiated from a common novel promoter located 587 kb upstream of exon 2, but did not contain the conserved region harboring rs7665116. Using real-time polymerase chain reaction, RNase protection assays and northern blotting, we show that the majority of these transcripts are brain specific and are at least equally or perhaps more abundant than the reference sequence PPARGC1A transcripts in whole brain. Two main transcripts containing independent methionine start codons encode full-length brain-specific PGC-1α proteins that differ only at their N-termini (NTs) from PGC-1α, encoded by the reference sequence. Additional truncated isoforms containing these NTs that are similar to NT-PGC-1α exist. Other transcripts may encode potential dominant negative forms, as they are predicted to lack the second LXXLL motif that serves as an interaction site for several nuclear receptors. Furthermore, we show that the new promoter is active in neuronal cell lines and describe haplotypes encompassing this region that are associated with HD age of onset. The discovery of such a large PPARGC1A genomic locus and multiple isoforms in brain warrants further functional studies and may provide new tissue-specific targets for treating neurodegenerative diseases.

An increase in extended-spectrum-␤-lactamase (ESBL)-producing Escherichia coli has been observed in outpatient settings. Consequently, 100 ESBL-positive E. coli isolates from ambulatory patients with clinically confirmed urinary tract infections were collected by a single laboratory between October 2004 and January 2008. Antimicrobial susceptibility testing was carried out using the oral antibiotics fosfomycin, pivmecillinam, and nitrofurantoin and the parenteral antibiotic ertapenem. Susceptibility rates indicate that fosfomycin (97%), nitrofurantoin (94%), and pivmecillinam (85%) could be considered important oral treatment options.

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Peroxisome proliferator-activated receptor ␥ coactivator-1␣ (PGC-1␣) is a transcriptional coactivator that contributes to the regulation of numerous transcriptional programs including the hepatic response to fasting. Mechanisms at transcriptional and post-transcriptional levels allow PGC-1␣ to support distinct biological pathways. Here we describe a novel human liver-specific PGC-1␣ transcript that results from alternative promoter usage and is induced by FOXO1 as well as glucocorticoids and cAMP-response element-binding protein signaling but is not present in other mammals. Hepatic tissue levels of novel and wild-type transcripts were similar but were only moderately associated (p < 0.003). Novel mRNA levels were associated with a polymorphism located in its promoter region, whereas wildtype transcript levels were not. Furthermore, hepatic PCK1 mRNA levels exhibited stronger associations with the novel than with the wild-type transcript levels. Except for a deletion of 127 amino acids at the N terminus, the protein, termed L-PGC-1␣, is identical to PGC-1␣. L-PGC-1␣ was localized in the nucleus and showed coactivation properties that overlap with those of PGC-1␣. Collectively, our data support a role of L-PGC-1␣ in gluconeogenesis, but functional differences predicted from the altered structure suggest that L-PGC-1␣ may have arisen to adapt PGC-1␣ to more complex metabolic pathways in humans. PGC-1␣2 (PPARGC1A) influences transcription in an exceptional variety of biological pathways including adaptive thermogenesis (1), mitochondrial biogenesis (2), skeletal muscle fiber determination and neuromuscular junction formation (3, 4), angiogenesis (5, 6), hepatic gluconeogenesis (7-9), fatty acid ␤-oxidation (10), regulation of clock genes (11), and protection of neural cells from reactive oxygen species (12, 13). Recent reviews describe the numerous functions of this fascinating protein (14 -17).Several levels of regulation have been implicated to explain the diverse roles of PGC-1␣ and its interactions with distinct transcription factors. For some pathways, expression levels of PGC-1␣ and transcription factors coactivated by PGC-1␣ are crucial (18). In addition, various signaling pathways target PGC-1␣ at the post-translational level. Such modifications detailed recently (19) alter the stability of PGC-1␣ and/or direct interactions with specific factors, thereby enhancing distinct transcriptional programs.Alternative splicing and/or transcription initiation, resulting in gain or deletion of interacting domains or signaling targets, represents another mode of regulation (15). Several PGC-1␣ isoforms have been reported in animal models (20,21). A short PGC-1␣ isoform was shown to be coexpressed with wild-type PGC-1␣ in mouse tissues and in human heart (22). The alternatively spliced mRNA is translated into a truncated protein, termed NT-PGC-1␣, that retains the N-terminal transactivation and nuclear receptor interaction domains and is functionally active.Knowledge about PGC-1␣ expression and regulation in human tissu...