SUMMARY Numerous studies in humans link a nonsynonymous genetic polymorphism (I148M) in adiponutrin (ADPN) to various forms of fatty liver disease and liver cirrhosis. Despite its high clinical relevance, the molecular function of ADPN and the mechanism by which I148M variant affects hepatic metabolism are unclear. Here we show that ADPN promotes cellular lipid synthesis by converting lysophosphatidic acid (LPA) into phosphatidic acid. The ADPN-catalyzed LPA acyltransferase (LPAAT) reaction is specific for LPA and long-chain acyl-CoAs. Wild-type mice receiving a high-sucrose diet exhibit substantial upregulation of Adpn in the liver and a concomitant increase in LPAAT activity. In Adpn-deficient mice, this diet-induced increase in hepatic LPAAT activity is reduced. Notably, the I148M variant of human ADPN exhibits increased LPAAT activity leading to increased cellular lipid accumulation. This gain of function provides a plausible biochemical mechanism for the development of liver steatosis in subjects carrying the I148M variant.
Comparative gene identification-58 (CGI-58), also designated as ␣/-hydrolase domain containing-5 (ABHD-5), is a lipid droplet-associated protein that activates adipose triglyceride lipase (ATGL) and acylates lysophosphatidic acid. Activation of ATGL initiates the hydrolytic catabolism of cellular triacylglycerol (TG) stores to glycerol and nonesterified fatty acids. Mutations in both ATGL and CGI-58 cause "neutral lipid storage disease" characterized by massive accumulation of TG in various tissues. The analysis of CGI-58-deficient (Cgi-58 ؊/؊ ) mice, presented in this study, reveals a dual function of CGI-58 in lipid metabolism. First, systemic TG accumulation and severe hepatic steatosis in newborn Cgi-58 ؊/؊ mice establish a limiting role for CGI-58 in ATGL-mediated TG hydrolysis and supply of nonesterified fatty acids as energy substrate. Second, a severe skin permeability barrier defect uncovers an essential ATGLindependent role of CGI-58 in skin lipid metabolism. The neonatal lethal skin barrier defect is linked to an impaired hydrolysis of epidermal TG. As a consequence, sequestration of fatty acids in TG prevents the synthesis of acylceramides, which are essential lipid precursors for the formation of a functional skin permeability barrier. This mechanism may also underlie the pathogenesis of ichthyosis in neutral lipid storage disease patients lacking functional CGI-58.Fatty acids (FA) 3 are major energy substrates and essential components of membrane lipids as well as of numerous bioactive lipid species. Because excessive cellular concentrations of nonesterified FA are toxic, eukaryotic cells detoxify them by esterification to triacylglycerols (TG), which are subsequently stored in cellular lipid droplets (LD). Adipose tissue is the major storage organ for TG. However, some LD are found in essentially all cell types and tissues. Depending on the nutritional status and the energy demand of an organism, TG are synthesized (lipogenesis) or catabolized (lipolysis). Defects in the control of the finely regulated balance between lipogenesis and lipolysis result in the development of metabolic disorders such as obesity, type II diabetes, lipodystrophy, and neutral lipid storage disease (NLSD) (1-6).Hydrolysis of TG is mediated by the enzymatic activity of adipose triglyceride lipase (ATGL) (7-9) and hormone-sensitive lipase (10, 11). Whereas hormone-sensitive lipase-deficient mice exhibit a relatively benign phenotype (12, 13), mice lacking ATGL massively accumulate TG in multiple tissues, exhibit a severe defect in energy metabolism, and die prematurely due to cardiac dysfunction (14). Similarly, humans with mutations in the ATGL gene lacking normal enzyme function develop NLSD associated with skeletal and cardiac myopathy (15). In severe cases, cardiomyopathy necessitates heart transplantation (16).Studies in this laboratory and by others demonstrated that both human and murine ATGL are stimulated by a protein designated as CGI-58 (comparative gene identification-58) (17, 18) or ABHD5 (␣/-hydrolase domain...
A nano-HPLC electrospray ionization multi-stage tandem mass spectrometry (nLC-ESI-MS/ MS) approach was applied to a complex crude triterpene saponin extract of Chenopodium quinoa seed coats. In ESI-MS/MS spectra of triterpene saponins, characteristic fragmentation reactions are observed and allow the determination of aglycones, saccharide sequences, compositions, and branching. Fragmentation of aglycones provided further structural information. The chemical complexity of the mixture was resolved by a complete profiling. Eighty-seven triterpene saponins comprising 19 reported and 68 novel components were identified and studied by MS. In addition to four reported, five novel triterpene aglycones were detected and characterized according to their fragmentation reactions in ESI-MS/MS and electron ionization mass spectrometry (EI-MS). As a novelty fragmentation pathways were proposed and analyzed based upon quantum chemical calculations using a hybrid HartreeFock density functional method. Accuracy of the assignment procedure was proven by isolation and structure determination of a novel compound. As the relative distribution and composition of saponins varies between different cultivars and soils, the presented strategy allows a rapid and complete analysis of Chenopodium quinoa saponin distribution and composition, and is particularly suitable for quality control and screening of extracts designated for pharmaceutical, agricultural, and industrial applications. (J Am Soc Mass Spectrom 2006, 17, 795-806)
Formation of eukaryotic ribosomes is driven by energy-consuming enzymes. The AAA-ATPase Drg1 is essential for the release of several shuttling proteins from cytoplasmic pre-60S particles and the loading of late joining proteins. However, its exact role in ribosome biogenesis has been unknown. Here we show that the shuttling protein Rlp24 recruited Drg1 to pre-60S particles and stimulated its ATPase activity. ATP hydrolysis in the second AAA domain of Drg1 was required to release shuttling proteins. In vitro, Drg1 specifically and exclusively extracted Rlp24 from purified pre-60S particles. Rlp24 release required ATP and was promoted by the interaction of Drg1 with the nucleoporin Nup116. Subsequent ATP hydrolysis in the first AAA domain dissociated Drg1 from Rlp24, liberating both proteins for consecutive cycles of activity. Our results show that release of Rlp24 by Drg1 defines a key event in large subunit formation that is a prerequisite for progression of cytoplasmic pre-60S maturation.
Mitochondrial outer membrane permeabilization is a watershed event in the process of apoptosis, which is tightly regulated by a series of pro-and anti-apoptotic proteins belonging to the BCL-2 family, each characteristically possessing a BCL-2 homology domain 3 (BH3). Here, we identify a yeast protein (Ybh3p) that interacts with BCL-X L and harbours a functional BH3 domain. Upon lethal insult, Ybh3p translocates to mitochondria and triggers BH3 domain-dependent apoptosis. Ybh3p induces cell death and disruption of the mitochondrial transmembrane potential via the mitochondrial phosphate carrier Mir1p. Deletion of Mir1p and depletion of its human orthologue (SLC25A3/PHC) abolish stress-induced mitochondrial targeting of Ybh3p in yeast and that of BAX in human cells, respectively. Yeast cells lacking YBH3 display prolonged chronological and replicative lifespans and resistance to apoptosis induction. Thus, the yeast genome encodes a functional BH3 domain that induces cell death through phylogenetically conserved mechanisms.
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