The metabolic syndrome is a cluster of metabolic and inflammatory abnormalities including obesity, insulin resistance, type 2 diabetes, hypertension, dyslipidemia, and atherosclerosis. The fatty acid binding proteins aP2 (fatty acid binding protein [FABP]-4) and mal1 (FABP5) are closely related and both are expressed in adipocytes. Previous studies in aP2-deficient mice have indicated a significant role for aP2 in obesity-related insulin resistance, type 2 diabetes, and atherosclerosis. However, the biological functions of mal1 are not known. Here, we report the generation of mice with targeted null mutations in the mal1 gene as well as transgenic mice overexpressing mal1 from the aP2 promoter/enhancer to address the role of this FABP in metabolic regulation in the presence or absence of obesity. To address the role of the second adipocyte FABP in metabolic regulation in the presence and deficiency of obesity, absence of mal1 resulted in increased systemic insulin sensitivity in two models of obesity and insulin resistance. Adipocytes isolated from mal1-deficient mice also exhibited enhanced insulin-stimulated glucose transport capacity. In contrast, mice expressing high levels of mal1 in adipose tissue display reduced systemic insulin sensitivity. Hence, our results demonstrate that mal1 modulates adipose tissue function and contributes to systemic glucose metabolism and constitutes a potential therapeutic target in insulin resistance. Diabetes 52:300 -307, 2003
Intracellular lipid-binding proteins are a family of low-molecularweight single-chain polypeptides that form 1:1 complexes with fatty acids, retinoids, or other hydrophobic ligands. These proteins are products of a large multigene family of unlinked loci distributed throughout the genome. Each lipid-binding protein exhibits a distinctive pattern of tissue distribution. Transcriptional control, regulated by a combination of peroxisome proliferator activated receptors and CCAAT/enhancer-binding proteins, allows for a variety of both cell and tissue-specific expression patterns. In some cells, fatty acids increase the expression of the lipid-binding protein genes. Fatty acids, or their metabolites, are activators of the peroxisome proliferator-activated receptor family of transcription factors. Therefore, as the concentration of lipid in the diet increases, the expression of lipid-binding proteins coordinately increases. As revealed by X-ray crystallography, the lipid-binding proteins fold into β-barrels, forming a large internal water-filled cavity. Fatty acid ligands are bound within the cavity, occupying only about one-third of the accessible volume. The bound fatty acid is stabilized via a combination of enthalpic and entropic forces that govern ligand affinity and selectivity. Cytoplasmic lipid-binding proteins are the intracellular receptors for hydrophobic ligands, delivering them to the appropriate site for use as metabolic fuels and regulatory agents.
4-Hydroxynonenal (4-HNE) is a cytotoxic
Agrobacterium tumefaciens VirB proteins are essential for gene transfer from bacteria to plants. These proteins are postulated to form a transport pore to allow transfer of the T-strand DNA intermediate. To study the function of the VirB proteins in DNA transfer, we developed an expression system in A. tumefaciens. Analysis of one VirB protein, VirB9, by Western blot assays showed that under nonreducing conditions VirB9, when expressed alone, migrates as a -31-kDa band but that it migrates as a -36-kDa band when expressed with all other VirB proteins. The 36-kDa band is converted to the 31-kDa band by the reducing agent 2-mercaptoethanol. Using strains that contain a deletion in a defined virB gene and strains that express specific VirB proteins, we demonstrate that the 36-kDa band is composed ofVirB9 and VirB7 that are linked to each other by a disulfide bond. Mutational studies demonstrate that cysteine residues at positions 24 of VirB7 and 262 of VirB9 participate in the formation of this complex.The transformation of a susceptible plant cell by the soil bacterium Agrobacterium tumefaciens results from the transfer and integration of a segment of the tumor-inducing (T,) plasmid DNA into the plant nuclear genome. The virulence (vir) genes of the Ti plasmid play an essential role in the DNA transfer and integration processes. The portion of the T1 plasmid that is transferred to plant cells (T-DNA) is defined by a 24-bp direct repeat sequence known as the border sequence. Two proteins of the virD operon, VirDl and VirD2, initiate the processing of the T-DNA by introducing a site-and strandspecific nick at the T-DNA borders, leading to the formation of a single-stranded T-strand DNA composed of the bottom strand of the T-DNA. The T-strand DNA contains a VirD2 molecule covalently attached to its 5'-end and is believed to be an intermediate in DNA transfer to plants (for reviews, see refs. 1 and 2).Little is known about the mechanism of DNA transfer from bacteria to plants. It is postulated that DNA transfer occurs through a transport pore primarily composed of the VirB proteins. Of the 11 VirB proteins, 10 (VirB2-VirB11) are essential for DNA transfer. The other protein (VirBl) is required for a high efficiency of DNA transfer (3). The observations that the VirB proteins have no role in T-strand DNA synthesis and that most of the VirB proteins are membrane associated led to their proposed role in DNA transfer (4-10). Subsequently, DNA sequence analysis of the trb genes of the conjugative plasmid pRP4 and that of the ptl operon of the pathogenic bacteria Bordetella pertussis revealed that these operons encode homologs of the VirB proteins (11,12). The requirement of the trb genes in conjugal transfer of plasmid DNA, that of the ptl genes in the secretion of the Bordetella toxin protein, and that of the virB genes in T-DNA transfer suggests the existence of a common transport pathway for macromolecule export. The requirement of the virB genes in tumor formation, in DNA transfer to plants in a transient DN...
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