Tuesday, November 4, 2008


As usual, kinda over my head. but does this relate to the failure of fructose to activate srebp's when compared to glucose?

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.


I came across SREBP when I was digging around reading about leptin; they did a study a while ago where they fed mice a leptin-free diet, and the mice lost all of their body fat within a few weeks. Leucine is more famous for it's anti-catabolic effect, promoting protein synthesis in muscles.

Leucine is a keto-protein; it can be made into fat, but not sugar. Fat can be used to synthesize cholesterol and steroids and stuff, and so can leucine. The presence of certain sterols is important in the synthesis of fatty acids. (Just don't ask me which sterols!) You can see how a very low fat diet that is also low in leucine might lower the production of fat cholesterol and sterols, and might thus make it hard to produce the very elements necessary to synthesize fats that might be used in turn to produce fat cholesterol and sterols... That is, if I'm at all following the plot here.

Maybe the catabolic effect of marathon-type exercise is related to this as well? But this time in muscle instead of fat?

Heres another one;


Overexpression of sterol regulatory element-binding protein-1a in mouse adipose tissue produces adipocyte hypertrophy, increased fatty acid secretion, and fatty liver.
Horton JD, Shimomura I, Ikemoto S, Bashmakov Y, Hammer RE.
Departments of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046, USA. Jay.horton@utsouthwestern.edu
Sterol regulatory element-binding proteins (SREBPs) are a family of membrane-bound transcription factors that regulate cholesterol and fatty acid homeostasis. In mammals, three SREBP isoforms designated SREBP-1a, SREBP-1c, and SREBP-2 have been identified. SREBP-1a and SREBP-1c are derived from the same gene by virtue of alternatively spliced first exons. SREBP-1a has a longer transcriptional activation domain and is a more potent transcriptional activator than SREBP-1c in cultured cells and liver. Here, we describe the physiologic consequences of overexpressing the nuclear form of SREBP-1a (nSREBP-1a) in adipocytes of mice using the adipocyte-specific aP2 promoter (aP2-nSREBP-1a). The transgenic aP2-nSREBP-1a mice developed markedly enlarged white and brown adipocytes that were fully differentiated. Adipocytes isolated from aP2-nSREBP-1a mice had significantly increased rates of fatty acid synthesis and enhanced fatty acid secretion. The increased production and release of fatty acids from adipocytes led, in turn, to a fatty liver. Overexpression of the alternative SREBP-1 isoform, nSREBP-1c, in adipose tissue inhibits adipocyte differentiation; as a result, the transgenic nSREBP-1c mice develop a syndrome resembling human lipodystrophy, which includes a loss of peripheral white adipose tissue, diabetes, and fatty livers (Shimomura, I., Hammer, R. E., Richardson, J. A., Ikemoto, S., Bashmakov, Y., Goldstein, J. L., and Brown, M. S. (1998) Genes Dev. 12, 3182-3194). In striking contrast, nSREBP-1a overexpression in fat resulted in the hypertrophy of fully differentiated adipocytes, no diabetes, and mild hepatic steatosis. These results suggest that nSREBP-1a and nSREBP-1c have distinct roles in adipocyte fat metabolism in vivo.
PMID: 12855691 [PubMed - indexed for MEDLINE]


One more study, quoted near the end of the last study;

Vol. 12, No. 20, pp. 3182-3194, October 15, 1998
RESEARCH PAPERInsulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy Iichiro Shimomura,1,4 Robert E. Hammer,2,4 James A. Richardson,3 Shinji Ikemoto,1 Yuriy Bashmakov,1 Joseph L. Goldstein,1,5 and Michael S. Brown1
1 Department of Molecular Genetics, 2 Department of Biochemistry and Howard Hughes Medical Institute, 3 Department of Pathology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235 USA
Overexpression of the nuclear form of sterol regulatory element-binding protein-1c (nSREBP-1c/ADD1) in cultured 3T3-L1 preadipocytes was shown previously to promote adipocyte differentiation. Here, we produced transgenic mice that overexpress nSREBP-1c in adipose tissue under the control of the adipocyte-specific aP2 enhancer/promoter. A syndrome with the following features was observed: (1) Disordered differentiation of adipose tissue. White fat failed to differentiate fully, and the size of white fat depots was markedly decreased. Brown fat was hypertrophic and contained fat-laden cells resembling immature white fat. Levels of mRNA encoding adipocyte differentiation markers (C/EBP, PPAR, adipsin, leptin, UCP1) were reduced, but levels of Pref-1 and TNF were increased. (2) Marked insulin resistance with 60-fold elevation in plasma insulin. (3) Diabetes mellitus with elevated blood glucose (>300 mg/dl) that failed to decline when insulin was injected. (4) Fatty liver from birth and elevated plasma triglyceride levels later in life. These mice exhibit many of the features of congenital generalized lipodystrophy (CGL), an autosomal recessive disorder in humans. http://www.ncbi.nlm.nih.gov/pubmed/12855691?ordinalpos=64&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

In the study itself, they mention that the plasma free fatty acids were not elevated; so they were not the source of the elevated triglycerides, and they suggest that free fatty acids synthesized in the liver itself went into those triglycerides. Do free fatty acids produced in the liver itself promote the production of glycogen and it's release? If the liver's ability to produce free fatty acids outstrips it's ability to produce triglycerides and this leads to increased blood sugar... Uh oh.

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