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Chylomicron and very low density lipoprotein (VLDL)1 remnants can be taken up via the endocytic ␣ 2 -macroglobulin receptor/LDL receptor-related protein (␣ 2 MR/LRP) either mediated by apolipoprotein E, or by lipoprotein lipase (LpL) or hepatic lipase associated with the lipoproteins (1-4). Recent results provide evidence that the uptake via ␣ 2 MR/LRP occurs in vivo, since remnant lipoproteins accumulate in mice that express reduced amounts of ␣ 2 MR/LRP and also lack functional LDL receptors (5). It has been suggested that the LpL-mediated pathway may be particularly important in the vascular wall, since ␣ 2 MR/LRP is abundant in macrophages and smooth muscle cells of atherosclerotic lesions and since LpL is secreted by macrophages in the lesions (6). In addition, it was recently shown that, whereas normal macrophages incubated with VLDL accumulate massive amounts of lipids, this does not occur in LpL-deficient macrophages (7). LpL binds to cell surface heparan sulfate proteoglycans (HSPG) as reflected in its strong affinity for binding to heparin. This property is physiologically important for the docking on endothelial cells exposing the lipase to circulating lipoproteins. LpL also binds to HSPG of other cell types as recently shown directly by immunofluorescence studies (8), and studies in Chinese hamster ovary cells have shown that uptake and degradation of LpL can be mediated by HSPG (9). In addition, the docking of LpL on HSPG of cells rich in ␣ 2 MR/LRP is important for uptake of LpL and for LpL-mediated uptake of lipoproteins via this receptor (4, 10, 11).LpL is a member of the mammalian lipase family also comprising the homologous hepatic and pancreatic lipases. The crystallographic structure of pancreatic lipase (12) shows that it consists of two folding domains, a larger N-terminal and a smaller C-terminal domain. Based upon the similarities in sequence it is thought that the domain organization is similar for LpL, and a three-dimensional model was recently proposed (13). LpL circulates both as a 96-kDa homodimer, which is the normally secreted and catalytically active form, and as a catalytically inactive monomer (14 -16). Although not known, it is likely that the LpL dimer is arranged head-to-tail in a way that allows enough space for conformational changes following substrate binding (13). The dimeric structure of LpL causes an increase in the affinity for heparin, presumably because sites in both monomers can participate in binding of one heparin molecule (13), and helps efficient ␣ 2 MR/LRP-mediated lipoprotein uptake, possibly because only the dimer can bind to a lipoprotein particle and to the receptor at the same time (10,17).The N-terminal folding domain of human LpL, comprising

The set of physiological and metabolic changes occurring immediately after inoculation and during the lag phase is thought to be of vital importance for optimal offset of fermentation. The transcriptional changes taking place during the lag phase after inoculation of a late-respiratory-phase yeast culture into fresh, minimal medium were investigated by use of Yeast GeneFilters. In response to the nutritional up-shift, 240 open reading frames were at least five-fold induced and 122 were at least five-fold repressed. These genes were hierarchically clustered according to their lag-phase expression patterns. The majority of the induced genes were most highly induced early in the lag phase, whereas strong repression generally occurred later. Clustering of the genes showed that many genes with similar roles had similar expression patterns. Repressed genes, however, did not cluster as tightly according to function as induced genes. Genes involved in RNA and protein synthesis and processing showed a peak in expression early in the lag phase, except most ribosomal protein genes, which were induced early and whose expression was sustained. Genes involved in chromatin/chromosome structure showed late induction. The correlation between function and expression pattern for these genes indicates regulation by similar mechanisms. Much of the transcriptional response observed appeared to be due to the presence of glucose in the new medium.

Aims:The aim of the present study is to identify genes and proteins whose expression is induced in lager brewing yeast during the lag phase and early exponential growth. Methods and Results: Two-dimensional gel electrophoresis was used to identify proteins induced during the lag and early exponential phase of lager brewing yeast in minimal medium. The identified, early-induced proteins were Ade17p, Eno2p, Ilv5gp, Sam1p, Rps21p and Ssa2p. For most of these proteins, the patterns of induction differed from those of the corresponding genes. However, the genes had similar early expression patterns in minimal medium as observed during lager brewing conditions. The expression of previously identified early-induced genes in Saccharomyces cerevisiae grown in minimal medium, ADO1, ALD6, ASC1, ERG4, GPP1, RPL25, SSB1 and YKL056C, was also early induced in lager yeast under brewing conditions. Conclusions: The results indicate that the above-mentioned genes in general are induced during the lag phase and early exponential growth in Saccharomyces yeasts. The processes in which these genes take part are likely to play an important role during growth initiation. Significance and Impact of the Study: Increased knowledge regarding the early growth phase of lager brewing yeast was obtained. Further, the universality of the identified expression patterns suggests new methodologies for optimization and control of growth initiation during brewing fermentations.

Summary NDG-4 is a predicted transmembrane acyltransferase protein which acts in the distribution of lipophilic factors. Consequently, ndg-4 mutants lay eggs with a pale appearance due to lack of yolk, and they are resistant to sterility caused by dietary supplementation with the long chain omega-6 polyunsaturated fatty acid dihommogamma-linolenic acid (DGLA). Two other proteins, NRF-5 and NRF-6, a homolog of a mammalian secreted lipid binding protein and a NDG-4 homolog, respectively, have previously been shown to function in the same lipid transport pathway. Here we report that mutation of the NDG-4 protein results in increased organismal stress resistance and lifespan. When NDG-4 function and insulin / IGF-1 signaling are reduced simultaneously, maximum lifespan is increased almost fivefold.Thus, longevity conferred by mutation of ndg-4 is partially overlapping with insulin signaling.The nuclear hormone receptor NHR-80 (HNF4 homolog) is required for longevity in germline less animals. We find that NHR-80 is also required for longevity of ndg-4 mutants. Moreover, we find that nrf-5 and nrf-6 mutants also have extended lifespan and increased stress resistance, suggesting that altered lipid transport and metabolism play key roles in determining lifespan.