Molecular Nutrition Unit

Stockholm, Sweden

Molecular Nutrition Unit

Stockholm, Sweden
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Iglesias J.,Molecular Nutrition Unit | Iglesias J.,University of Montréal | Iglesias J.,Pontifical Xavierian University | Lamontagne J.,Molecular Nutrition Unit | And 16 more authors.
Journal of Lipid Research | Year: 2016

Lipids are used as cellular building blocks and condensed energy stores and also act as signaling molecules. The glycerolipid/fatty acid cycle, encompassing lipolysis and lipogenesis, generates many lipid signals. Reliable procedures are not available for measuring activities of several lipolytic enzymes for the purposes of drug screening, and this resulted in questionable selectivity of various known lipase inhibitors. We now describe simple assays for lipolytic enzymes, including adipose triglyceride lipase (ATGL), hormone sensitive lipase (HSL), sn -1-diacylglycerol lipase (DAGL), monoacylglycerol lipase, α/β-hydrolase domain 6, and carboxylesterase 1 (CES1) using recombinant human and mouse enzymes either in cell extracts or using purified enzymes. We observed that many of the reported inhibitors lack specificity. Thus, Cay10499 (HSL inhibitor) and RHC20867 (DAGL inhibitor) also inhibit other lipases. Marked differences in the inhibitor sensitivities of human ATGL and HSL compared with the corresponding mouse enzymes was noticed. Thus, ATGListatin inhibited mouse ATGL but not human ATGL, and the HSL inhibitors WWL11 and Compound 13f were effective against mouse enzyme but much less potent against human enzyme. Many of these lipase inhibitors also inhibited human CES1. Results describe reliable assays for measuring lipase activities that are amenable for drug screening and also caution about the specificity of the many earlier described lipase inhibitors. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.


Ghosh M.,Metabolism Unit | Ghosh M.,Molecular Nutrition Unit | Ghosh M.,Karolinska Institutet | Ghosh M.,Karolinska University Hospital | And 11 more authors.
Journal of Lipid Research | Year: 2015

Pharmacologically increased estrogen levels have been shown to lower hepatic and plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels in animals and humans. We hypothesized that physiological changes in estrogen levels infl uence circulating PCSK9, thereby contributing to the known wide inter-individual variation in its plasma levels, as well as to the established increase in LDL cholesterol (LDL-C) with normal aging. Circulating PCSK9, estradiol, and other metabolic factors were determined in fasting samples from 206 female and 189 male healthy volunteers (age 20-85 years), The mean levels of PCSK9 were 10% higher in females than in males ( P < 0.05). PCSK9 levels were 22% higher in postmenopausal than in premenopausal ( P < 0.001) females. Within the group of premenopausal females, circulating PCSK9 correlated inversely to estrogen levels, and PCSK9 was higher (305 ng/ml) in the follicular phase than in the ovulatory (234 ng/ml) or the luteal (252 ng/ml) phases ( P < 0.05). Changes in endogenous estrogen levels during the menstrual cycle likely contribute to the broad interindividual variation in PCSK9 and LDL-C in normal females. PCSK9 levels increase in females after menopause but not in men during this phase in life. This likely contributes to why LDL-C in women increases in this period. -Ghosh, M., C. Gälman, M. Rudling, and B. Angelin. Infl uence of physiological changes in endogenous estrogen on circulating PCSK9 and LDL cholesterol. J. Lipid Res. © 2015 by the American Society for Biochemistry and Molecular Biology Inc.

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