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Journal of Lipid Research

Lila M Gierasch, Nicholas O Davidson, Kerry-Anne Rye, Alma L Burlingame
February 13, 2019: Journal of Lipid Research
Jihong Lian, Russell Watts, Ariel D Quiroga, Megan R Beggs, R Todd Alexander, Richard Lehner
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. TG accumulation in liver is a hallmark of NAFLD. Metabolic studies have confirmed that increased hepatic de novo lipogenesis in humans contributes to fat accumulation in the liver and to NAFLD progression. Mice deficient in carboxylesterase 1d (Ces1d) expression are protected from high-fat diet-induced hepatic steatosis. To investigate whether loss of Ces1d can also mitigate steatosis induced by over-activated de novo lipogenesis, wild type and Ces1d deficient mice were fed a lipogenic high-sucrose diet...
February 8, 2019: Journal of Lipid Research
Andrew A Butler, Candice A Price, James L Graham, Kimber L Stanhope, Sarah King, Yu-Han Hung, Praveen Sethupathy, So Wong, James Hamilton, Ronald M Krauss, Andrew A Bremer, Peter J Havel
Dyslipidemia and insulin resistance are significant adverse outcomes of consuming high-sugar diets. Conversely, dietary fish oil reduces plasma lipids. Diet-induced dyslipidemia in a rhesus model better approximates the pathophysiology of human metabolic syndrome than rodent models. Here we investigated relationships between metabolic parameters and hypertriglyceridemia in rhesus macaques consuming a high fructose diet (n=59) and determined effects of fish oil supplementation or RNA interference (RNAi) on plasma apoC3 and TG concentrations...
February 5, 2019: Journal of Lipid Research
Richard Wagner, Julia Dittrich, Joachim Thiery, Uta Ceglarek, Ralph Burkhardt
Apolipoproteins are major structural and functional constituents of lipoprotein particles. As modulators of lipid metabolism, adipose tissue biology, and energy homeostasis, apolipoproteins may serve as biomarkers or potential therapeutic targets for cardiometabolic diseases. Mice are the preferred model to study metabolic and cardiovascular disease, but a comprehensive method to quantify circulating apolipoproteins in mice is lacking. We developed and validated a targeted proteomics assay to quantify eight apolipoproteins in mice via proteotypic signature peptides and corresponding stable isotope labelled analogs...
February 5, 2019: Journal of Lipid Research
Lori Begaye, Judith A Simcox
No abstract text is available yet for this article.
February 4, 2019: Journal of Lipid Research
Marcia N Paddock, Seth J Field, Lewis C Cantley
The discovery of the phosphatidylinositol-3-kinase (PI3K) pathway was a major advance in understanding growth factor signaling. The high frequency of PI3K pathway mutations in many cancers has encouraged a new field targeting cancer driver mutations. Although there have been many successes, targeting PI3K itself has proven challenging, in part because of its multiple isoforms with distinct roles. Despite promising preclinical results, development of PI3K inhibitors as pharmacologic anticancer agents has been limited by modest single-agent efficacy and significant adverse effects...
February 4, 2019: Journal of Lipid Research
Fabrizio Vacca, Stefania Vossio, Vincent Mercier, Dimitri Moreau, Shem Johnson, Cameron C Scott, Jonathan Paz Montoya, Marc Moniatte, Jean Gruenberg
In specialized cell types, lysosome-related organelles support regulated secretory pathways, while in non-specialized cells, lysosomes can undergo fusion with the plasma membrane in response to a transient rise in cytosolic calcium. Recent evidence also indicates that lysosome secretion can be controlled transcriptionally and promote clearance in lysosome storage diseases. In addition, evidence is also accumulating that low concentrations of cyclodextrins reduce the cholesterol storage phenotype in cells and animals with the cholesterol storage disease Niemann-Pick type C, via an unknown mechanism...
February 1, 2019: Journal of Lipid Research
Kyoung-Jae Won, Joo-Seop Park, Hyunyoung Jeong
All- trans retinoic acid (atRA) is used to treat certain cancers or dermatologic diseases. A common adverse effect of atRA is hypercholesterolemia; cytochrome P450 (CYP) 7A repression is suggested as a driver. However, the underlying molecular mechanisms remain unclear. We investigated CYP7A1 expression in the presence of atRA in human hepatocytes and hepatic cell lines. In HepaRG cells, atRA increased cholesterol levels dose dependently alongside dramatic decreases in CYP7A1 expression. Lentivrial-mediated CYP7A1 overexpression reversed atRA-induced cholesterol accumulation, suggesting that CYP7A1 repression mediated cholesterol accumulation...
February 1, 2019: Journal of Lipid Research
Wenxu Zhou, Emilio Ramos, Xunlu Zhu, Paxtyn M Fisher, Medhanie E Kidane, Boden H Vanderloop, Crista D Thomas, Juqiang Yan, Ujjal Singha, Minu Chaudhuri, Michael T Nagel, W David Nes
Pathogenic organisms may be sensitive to inhibitors of sterol biosynthesis, which carry antimetabolite properties, through manipulation of the key enzyme sterol methyltransferase (SMT). Here, we isolated natural suicide substrates of the ergosterol biosynthesis pathway - cholesta-5,7,22,24-tetraenol (CHT) and ergosta-5,7,22,24(28)-tetraenol (ERGT) and demonstrated their interference in Acanthamoeba castellanni steroidogenesis: CHT and ERGT inhibit trophozoite growth (EC50 of 51 nM) without affecting cultured human cell growth...
February 1, 2019: Journal of Lipid Research
Kacey J Prentice, Jani Saksi, Gokhan S Hotamisligil
While counter regulatory hormones and mediators of the fight-or-flight responses are well defined at many levels, how energy stores per-se are integrated into this system remains an enigmatic question. Recent years have seen the adipose tissue become a central focus for mediating intracellular signaling and communication through the release of a variety of bioactive lipids and substrates, as well as various adipokines. A critical integration node among these mediators and responses is controlled by fatty acid binding protein 4 (FABP4), also known as adipocyte protein 2 (aP2), which is highly expressed in adipose tissue and functions as a lipid chaperone protein...
January 30, 2019: Journal of Lipid Research
Cornelia Pipper, Natalie Bordag, Bernadette Reiter, Kyriakos Economides, Peter Florian, Thomas Birngruber, Frank Sinner, Manfred Bodenlenz, Anita Eberl
Eicosanoids are lipid mediator molecules with key roles in inflammatory skin diseases such as psoriasis. Eicosanoids are released close to the source of inflammation where they elicit local, pleiotropic effects and dysregulations. Monitoring inflammatory mediators directly in skin lesions could provide new insights and new therapeutic possibilities. This study describes the analysis of dermal interstitial fluid (dISF) samples obtained by dermal open flow microperfusion (dOFM) in a rat model of skin inflammation...
January 29, 2019: Journal of Lipid Research
Gabor Jozsef Tigyi, Leonard R Johnson, Sue Chin Lee, Derek D Norman, Erzsebet Szabo, Andrea Balogh, Karin Thompson, Alyssa L Boler, Shannon W McCool
The growth factor-like lipid mediator lysophosphatidic acid (LPA) is a potent signaling molecule that influences numerous physiologic and pathologic processes. Manipulation of LPA signaling is of growing pharmacotherapeutic interest, especially because LPA resembles compounds with drug-like features. LPA action is mediated through activation of multiple types of molecular targets including six G-protein-coupled receptors - clear targets for drug development. However, the LPA signaling has been linked to pathological responses which include promotion of fibrosis, atherogenesis, tumorigenesis, and metastasis...
January 28, 2019: Journal of Lipid Research
Oleg Kovrov, Kristian K Kristensen, Erika Larsson, Michael Ploug, Gunilla Olivecrona
Angiopoietin-like (ANGPTL) 8 is a secreted inhibitor of lipoprotein lipase (LPL), a key enzyme in plasma triglyceride metabolism. It was previously reported that ANGPTL8 requires another member of the ANGPTL family, ANGPTL3, to act on lipoprotein lipase. ANGPTL3, much like ANGPTL4, is a physiologically relevant regulator of LPL activity, which causes irreversible inactivation of the enzyme. Here we show that ANGPTL8 can form complexes with either ANGPTL3 or ANGPTL4 when the proteins are refolded together from their denatured states...
January 27, 2019: Journal of Lipid Research
Rosalind A Coleman
Diet, hormones, gene transcription, and post-translational modifications control the hepatic metabolism of FAs; metabolic dysregulation causes chronic diseases, including cardiovascular disease, and warrants exploration into the mechanisms directing FA and triacylglycerol (TAG) synthesis and degradation. Long-chain FA metabolism begins by formation of an acyl-CoA by a member of the acyl-CoA synthetase family (ACSL). Subsequently, TAG synthesis begins with acyl-CoA esterification to glycerol-3-phosphate by a member of the glycerol-3-phosphate acyltransferase (GPAT) family...
January 25, 2019: Journal of Lipid Research
Teresa M Dunn, Cynthia J Tifft, Richard L Proia
The sphingolipid (SL) metabolic pathway generates structurally diverse lipids that have roles as membrane constituents and as bioactive signaling molecules. The influence of the SL metabolic pathway in biology is pervasive; it exists in all mammalian cells and has roles in many cellular and physiological pathways. Human genetic diseases have long been recognized to be caused by mutations in the pathway, but until recently these mutational defects were only known to affect lysosomal SL degradation. Now, with a nearly complete delineation of the genes constituting the SL metabolic pathway, a growing number of additional genetic disorders caused by mutations in genes within other sectors of the pathway - de novo ceramide synthesis, glycosphingolipid synthesis, and non-lysosomal SL degradation - have been recognized...
January 25, 2019: Journal of Lipid Research
Mei Zhou, Marc Learned, Stephen J Rossi, Hui Tian, Alex M DePaoli, Lei Ling
FGF19, an endocrine hormone produced in the gut, acts in the liver to control bile acid synthesis. NGM282, an engineered FGF19 analogue, is currently in clinical development for treating non-alcoholic steatohepatitis. However, the molecular mechanisms that integrate FGF19 with cholesterol metabolic pathways are incompletely understood. Here we report that FGF19 and NGM282 promote HDL biogenesis and cholesterol efflux from the liver by selectively modulating liver X receptor signaling while ameliorating hepatic steatosis...
January 24, 2019: Journal of Lipid Research
Cheng Chen, Jibiao Li, David J Matye, Yifeng Wang, Tiangang Li
Sortilin 1 (Sort1) is a member of the Vps10p domain intracellular trafficking receptor family. Genetic variations of SORT1 gene is strongly associated with plasma cholesterol levels in humans. Recent studies have linked Sort1 to regulation of cholesterol metabolism in hepatocytes and pro-inflammatory response in macrophages, but tissue-specific roles of Sort1 in lipid metabolism have not been well defined. We developed Sort1 floxed mice and investigated the development of Western diet (WD)-induced steatosis, hepatic inflammatory response and hyperlipidemia in hepatocyte Sort1 KO mice and myeloid cell Sort1 KO mice...
January 22, 2019: Journal of Lipid Research
Matthew G McDonald, Catherine K Yeung, Aaron M Teitelbaum, Amanda L Johnson, Shinya Fujii, Hiroyuki Kagechika, Allan E Rettie
Vitamin K, in both its phylloquinone and menaquinone forms, has been hypothesized to undergo ω- and β-oxidation on its hydrophobic side chain in order to generate the observed urinary metabolites, K Acid I and K Acid II, which are excreted primarily as glucuronide conjugates. Synthetic standards of K Acid I, K Acid II and a putative intermediate metabolite, MK1 ω-COOH, were used to develop and optimize a new APCI- LC-MS/MS assay for the quantitation of these compounds in urine from untreated individuals and subjects treated with a high dose vitamin K supplement...
January 22, 2019: Journal of Lipid Research
Sergei A Novgorodov, Joshua R Voltin, Wenxue Wang, Stephen Tomlinson, Christopher L Riley, Tatyana I Gudz
Traumatic brain injury (TBI) is one of the leading causes of disability worldwide and a prominent risk factor for neurodegenerative diseases. The expansion of nervous tissue damage after the initial trauma involves a multifactorial cascade of events including excitotoxicity, oxidative stress, inflammation and deregulation of sphingolipid metabolism that further mitochondrial dysfunction and secondary brain damage. Here, we show a post-transcriptional activation of an acid sphingomyelinase (ASM), a key enzyme of the sphingolipid recycling pathway, resulted in a selective increase of sphingosine in mitochondria during the first week post-TBI that was accompanied by reduced activity of mitochondrial cytochrome oxidase and activation of the NLRP3 inflammasome...
January 20, 2019: Journal of Lipid Research
Yun Li, Ping Yang, Lei Zhao, Yao Chen, Xiaoyu Zhang, Shu Zeng, Li Wei, Zac Varghese, John F Moorhead, Yaxi Chen, Xiong Z Ruan
Fatty acid translocase CD36 (CD36) is a multifunctional membrane protein that facilitates the uptake of long-chain fatty acid (LCFA). Lipophagy is autophagic degradation of lipid droplets. Accumulating evidence suggests that CD36 is involved in the regulation of intracellular signal transduction that modulates fatty acid storage or usage. However, little is known about the relationship between CD36 and lipophagy. In this study, we found that increasedCD36 expression was coupled with decreasedautophagy in the livers of mice treated with a high-fat diet...
January 20, 2019: Journal of Lipid Research
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