Antidiabetic plants and their active constituents.

Oxygenated derivatives of cholesterol (oxysterols) present a remarkably diverse profile of biological activities, including effects on sphingolipid metabolism, platelet aggregation, apoptosis, and ...

Oxysterols: modulators of cholesterol metabolism and other processes.

The hallmarks of cancer metabolism: Still emerging.

The ability to regulate specific genes of energy metabolism in response to fasting and feeding is an important adaptation allowing survival of intermittent food supplies. However, little is known about transcription factors involved in such responses in higher organisms. We show here that gene expression in adipose tissue for adipocyte determination differentiation dependent factor (ADD) 1/sterol regulatory element binding protein (SREBP) 1, a basic-helix-loop-helix protein that has a dual DNA-binding specificity, is reduced dramatically upon fasting and elevated upon refeeding; this parallels closely the regulation of two adipose cell genes that are crucial in energy homeostasis, fatty acid synthetase (FAS) and leptin. This elevation of ADD1/SREBP1, leptin, and FAS that is induced by feeding in vivo is mimicked by exposure of cultured adipocytes to insulin, the classic hormone of the fed state. We also show that the promoters for both leptin and FAS are transactivated by ADD1/SREBP1. A mutation in the basic domain of ADD1/SREBP1 that allows E-box binding but destroys sterol regulatory element-1 binding prevents leptin gene transactivation but has no effect on the increase in FAS promoter function. Molecular dissection of the FAS promoter shows that most if not all of this action of ADD1/SREBP1 is through an E-box motif at -64 to -59, contained with a sequence identified previously as the major insulin response element of this gene. These results indicate that ADD1/SREBP1 is a key transcription factor linking changes in nutritional status and insulin levels to the expression of certain genes that regulate systemic energy metabolism.

/pdf/nutritional-and-insulin-regulation-of-fatty-acid-synthetase-2qvrut3bm7.pdf

Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1/SREBP1.

Hepatic glucokinase plays a key role in glucose metabolism as underlined by the anomalies associated with glucokinase mutations and the consequences of tissue-specific knock-out. In the liver, glucokinase transcription is absolutely dependent on the presence of insulin. The cis-elements and trans-acting factors that mediate the insulin effect are presently unknown; this is also the case for most insulin-responsive genes. We have shown previously that the hepatic expression of the transcription factor sterol regulatory element binding protein-1c (SREBP-1c) is activated by insulin. We show here in primary cultures of hepatocytes that the adenovirus-mediated transduction of a dominant negative form of SREBP-1c inhibits the insulin effect on endogenous glucokinase expression. Conversely, in the absence of insulin, the adenovirus-mediated transduction of a dominant positive form of SREBP-1c overcomes the insulin dependency of glucokinase expression. Hepatic fatty acid synthase and Spot-14 are insulin/glucose-dependent genes. For this latter class of genes, the dominant positive form of SREBP-1c obviates the necessity for the presence of insulin, whereas glucose potentiates the effect of SREBP-1c on their expression. In addition, the insulin dependency of lipid accumulation in cultured hepatocytes is overcome by the dominant positive form of SREBP-1c. We propose that SREBP-1c is a major mediator of insulin action on hepatic gene expression and a key regulator of hepatic glucose/lipid metabolism.

https://www.pnas.org/content/pnas/96/22/12737.full.pdf

Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes

The organization of the gene of the human myelin basic protein has been established. The gene contains seven exons distributed over 32-34 kb. The nucleotide sequences of the seven exons, extensive parts at the 5' noncoding region and upstream and downstream regions adjacent to the exons were sequenced. A comparison of the nucleotide sequence of the human gene with mouse MBP cDNA and parts of the gene structure of mouse MBP has been carried out. There is a high degree of conservation in the seven exons and the 5'-regulatory and part of the 3'-noncoding region: the nucleotide sequence of the coding region of the human and mouse gene show a 93% homology. As far as the reported 5'-noncoding and upstream regulatory regions of 478 bp are comparable these regions are more than 80% homologous. Primer extension experiments positioned the transcription initiation sites at -55, -82 and -183. In the 5'-regulatory region of MBP gene three direct repeats were found, a nonameric at -401/-416 and two octameric at -192/-216 and -492/-508. A decameric sequence (-256 to -265 from the translation start) is completely homologous to a sequence of the human PLP regulatory 5'-noncoding region.

The organization of the human myelin basic protein gene. Comparison with the mouse gene.

A single nucleotide substitution in the promoter region of the apolipoprotein C-II gene identified in individuals with chylomicronemia.

Insulin resistance is an essential feature of a great variety of clinical disorders, like diabetes mellitus, obesity, essential hypertension, and is primarily due to a defect in hormone action at the cellular level. In the past decade application of novel research techniques including recombinant DNA technology have paved the way to understand the mechanisms of insulin action and its alterations at the molecular level. The first step in insulin action is the activation of the insulin receptor. The insulin receptor is a tetrameric protein consisting of two extracellular alpha- and two transmembrane beta-subunits. Binding of insulin to the alpha-subunit causes autophosphorylation of the intracellular beta-subunit region on tyrosine residues thereby activating the receptor. How the hormonal signal is subsequently transduced within the cell is still quiet unclear. The activated insulin receptor appears to couple to cytosolic receptor substrates which can affect different signaling cascades eliciting the pleiotropic hormone response on cell metabolism and growth. Most proteins involved in the signal transduction pathway of insulin are not known yet, but each of them might play a role in the various forms of insulin resistance. Taking the insulin receptor as an exemplary protein involved in insulin action we review molecular mechanisms regulating insulin receptor activity, gene expression, and the role of natural occurring insulin receptor gene mutations in patients with insulin resistant diabetes mellitus. It is outlined how the combination of both clinical medicine and molecular biology not only helps to understand insulin action and the pathogenesis of insulin resistance, but also leads to new avenues in the differential diagnosis, therapy, and possibly prevention of this heterogenous but most frequent metabolic and endocrine disorder.

Molecular biology of insulin resistance.

Defects of insulin and IGF-1 action at receptor and postreceptor level in a patient with type A syndrome of insulin resistance.

Promoter activity of the LDL receptor gene is stimulated by insulin and estradiol and mediated by SRE-1, which acts as a hormone sensitive cis-elemente. Using the antisense technique we reveal that SREBP-1 is selectively involved in the signal transduction pathway of insulin and IGF-I.

Regulation of the LDL receptor gene expression by hormones.

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