Author
Sylvaine Cases
Other affiliations: University of California, Veterans Health Administration, Gladstone Institutes
Bio: Sylvaine Cases is an academic researcher from University of California, San Francisco. The author has contributed to research in topics: Sterol O-acyltransferase & Nucleic acid. The author has an hindex of 17, co-authored 29 publications receiving 5749 citations. Previous affiliations of Sylvaine Cases include University of California & Veterans Health Administration.
Papers
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TL;DR: This work demonstrates in cultured cells that the relative toxicity of two common dietary long chain fatty acids is related to channeling of these lipids to distinct cellular metabolic fates, and supports a model of cellular lipid metabolism in which unsaturated fatty acids serve a protective function against lipotoxicity though promotion of triglyceride accumulation.
Abstract: Excess lipid accumulation in non-adipose tissues is associated with insulin resistance, pancreatic β-cell apoptosis and heart failure. Here, we demonstrate in cultured cells that the relative toxicity of two common dietary long chain fatty acids is related to channeling of these lipids to distinct cellular metabolic fates. Oleic acid supplementation leads to triglyceride accumulation and is well tolerated, whereas excess palmitic acid is poorly incorporated into triglyceride and causes apoptosis. Unsaturated fatty acids rescue palmitate-induced apoptosis by channeling palmitate into triglyceride pools and away from pathways leading to apoptosis. Moreover, in the setting of impaired triglyceride synthesis, oleate induces lipotoxicity. Our findings support a model of cellular lipid metabolism in which unsaturated fatty acids serve a protective function against lipotoxicity though promotion of triglyceride accumulation.
1,724 citations
TL;DR: An expressed sequence tag clone that shared regions of similarity with acyl CoA:cholesterol acyltransferase, an enzyme that also uses fatty acyl coA as a substrate was identified, which will greatly facilitate studies of cellular glycerolipid metabolism and its regulation.
Abstract: Triacylglycerols are quantitatively the most important storage form of energy for eukaryotic cells Acyl CoA:diacylglycerol acyltransferase (DGAT, EC 23120) catalyzes the terminal and only committed step in triacylglycerol synthesis, by using diacylglycerol and fatty acyl CoA as substrates DGAT plays a fundamental role in the metabolism of cellular diacylglycerol and is important in higher eukaryotes for physiologic processes involving triacylglycerol metabolism such as intestinal fat absorption, lipoprotein assembly, adipose tissue formation, and lactation DGAT is an integral membrane protein that has never been purified to homogeneity, nor has its gene been cloned We identified an expressed sequence tag clone that shared regions of similarity with acyl CoA:cholesterol acyltransferase, an enzyme that also uses fatty acyl CoA as a substrate Expression of a mouse cDNA for this expressed sequence tag in insect cells resulted in high levels of DGAT activity in cell membranes No other acyltransferase activity was detected when a variety of substrates, including cholesterol, were used as acyl acceptors The gene was expressed in all tissues examined; during differentiation of NIH 3T3-L1 cells into adipocytes, its expression increased markedly in parallel with increases in DGAT activity The identification of this cDNA encoding a DGAT will greatly facilitate studies of cellular glycerolipid metabolism and its regulation
1,117 citations
TL;DR: It is shown that Dgat-deficient (Dgat−/−) mice are viable and can still synthesize triglycerides, and these mice are lean and resistant to diet-induced obesity.
Abstract: Triglycerides (or triacylglycerols) represent the major form of stored energy in eukaryotes Triglyceride synthesis has been assumed to occur primarily through acyl CoA:diacylglycerol transferase (Dgat), a microsomal enzyme that catalyses the final and only committed step in the glycerol phosphate pathway Therefore, Dgat has been considered necessary for adipose tissue formation and essential for survival Here we show that Dgat-deficient (Dgat-/-) mice are viable and can still synthesize triglycerides Moreover, these mice are lean and resistant to diet-induced obesity The obesity resistance involves increased energy expenditure and increased activity Dgat deficiency also alters triglyceride metabolism in other tissues, including the mammary gland, where lactation is defective in Dgat-/- females Our findings indicate that multiple mechanisms exist for triglyceride synthesis and suggest that the selective inhibition of Dgat-mediated triglyceride synthesis may be useful for treating obesity
918 citations
TL;DR: A second mammalian DGAT, DGAT2, is cloned and characterized, which was identified by its homology to a DGAT in the fungus Mortierella rammaniana, suggesting that it may play a significant role in mammalian triglyceride metabolism.
805 citations
TL;DR: A second mammalian ACAT enzyme is described, designated ACAT-2, that is 44% identical to the first cloned mouse ACAT (henceforth designated ACat-1) and will facilitate molecular approaches to understanding the role of ACAT enzymes in mammalian biology.
386 citations
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TL;DR: Induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions is demonstrated and iPS cells, designated iPS, exhibit the morphology and growth properties of ES cells and express ES cell marker genes.
23,959 citations
TL;DR: iPS cells competent for germline chimaeras can be obtained from fibroblasts, but retroviral introduction of c-Myc should be avoided for clinical application.
Abstract: We have previously shown that pluripotent stem cells can be induced from mouse fibroblasts by retroviral introduction of Oct3/4 (also called Pou5f1), Sox2, c-Myc and Klf4, and subsequent selection for Fbx15 (also called Fbxo15) expression These induced pluripotent stem (iPS) cells (hereafter called Fbx15 iPS cells) are similar to embryonic stem (ES) cells in morphology, proliferation and teratoma formation; however, they are different with regards to gene expression and DNA methylation patterns, and fail to produce adult chimaeras Here we show that selection for Nanog expression results in germline-competent iPS cells with increased ES-cell-like gene expression and DNA methylation patterns compared with Fbx15 iPS cells The four transgenes (Oct3/4, Sox2, c-myc and Klf4) were strongly silenced in Nanog iPS cells We obtained adult chimaeras from seven Nanog iPS cell clones, with one clone being transmitted through the germ line to the next generation Approximately 20% of the offspring developed tumours attributable to reactivation of the c-myc transgene Thus, iPS cells competent for germline chimaeras can be obtained from fibroblasts, but retroviral introduction of c-Myc should be avoided for clinical application
4,371 citations
TL;DR: Nanog is a critical factor underlying pluripotency in both ICM and ES cells, and it is found that one of them, encoding the homeoprotein Nanog, was capable of maintaining ES cell self-renewal independently of LIF/Stat3.
3,321 citations
TL;DR: A modified protocol for the generation of iPS cells that does not require the Myc retrovirus is described and, with this protocol, significantly fewer non-iPS background cells are obtained, and theiPS cells generated were consistently of high quality.
Abstract: Direct reprogramming of somatic cells provides an opportunity to generate patient- or disease-specific pluripotent stem cells. Such induced pluripotent stem (iPS) cells were generated from mouse fibroblasts by retroviral transduction of four transcription factors: Oct3/4, Sox2, Klf4 and c-Myc. Mouse iPS cells are indistinguishable from embryonic stem (ES) cells in many respects and produce germline-competent chimeras. Reactivation of the c-Myc retrovirus, however, increases tumorigenicity in the chimeras and progeny mice, hindering clinical applications. Here we describe a modified protocol for the generation of iPS cells that does not require the Myc retrovirus. With this protocol, we obtained significantly fewer non-iPS background cells, and the iPS cells generated were consistently of high quality. Mice derived from Myc(-) iPS cells did not develop tumors during the study period. The protocol also enabled efficient isolation of iPS cells without drug selection. Furthermore, we generated human iPS cells from adult dermal fibroblasts without MYC.
2,974 citations
TL;DR: The last 5 years of the millennium have witnessed a dramatic increase in understanding of the biology of regulated energy balance and body weight, and insights from the sequencing of the human genome and the coming advances in proteomics are likely to fuel the next wave of progress.
2,332 citations