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Start Over Descriptor "&nbsp" Journal journal of lipid research
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1. Direct anabolic metabolism of three-carbon propionate to a six-carbon metabolite occurs in vivo across tissues and species

Author

Doan, Mary T, Neinast, Michael D, Varner, Erika L, Bedi, Kenneth C, Bartee, David, Jiang, Helen, Trefely, Sophie, Xu, Peining, Singh, Jay P, Jang, Cholsoon, Rame, J Eduardo, Brady, Donita C, Meier, Jordan L, Marguiles, Kenneth B, Arany, Zoltan, and Snyder, Nathaniel W

Subjects
Digestive Diseases, Biotechnology, Acetyl Coenzyme A, Acyl Coenzyme A, Animals, Carbon, Liver, Mice, Oxidation-Reduction, Propionates, &nbsp, Metabolism, propionate, anabolism, acetyl-CoA, condensation reaction, stable isotope tracing, LC-MS, HRMS, TCA cycle, valine, 2M2PE-CoA, LC-MS/HRMS, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Biochemistry & Molecular Biology
Abstract

Anabolic metabolism of carbon in mammals is mediated via the one- and two-carbon carriers S-adenosyl methionine and acetyl-coenzyme A. In contrast, anabolic metabolism of three-carbon units via propionate has not been shown to extensively occur. Mammals are primarily thought to oxidize the three-carbon short chain fatty acid propionate by shunting propionyl-CoA to succinyl-CoA for entry into the TCA cycle. Here, we found that this may not be absolute as, in mammals, one nonoxidative fate of propionyl-CoA is to condense to two three-carbon units into a six-carbon trans-2-methyl-2-pentenoyl-CoA (2M2PE-CoA). We confirmed this reaction pathway using purified protein extracts provided limited substrates and verified the product via LC-MS using a synthetic standard. In whole-body in vivo stable isotope tracing following infusion of 13C-labeled valine at steady state, 2M2PE-CoA was found to form via propionyl-CoA in multiple murine tissues, including heart, kidney, and to a lesser degree, in brown adipose tissue, liver, and tibialis anterior muscle. Using ex vivo isotope tracing, we found that 2M2PE-CoA also formed in human myocardial tissue incubated with propionate to a limited extent. While the complete enzymology of this pathway remains to be elucidated, these results confirm the in vivo existence of at least one anabolic three- to six-carbon reaction conserved in humans and mice that utilizes propionate.

Published
2022

2. GOLM1 depletion modifies cellular sphingolipid metabolism and adversely affects cell growth

Author

Meghana Nagaraj, Marcus Höring, Maria A. Ahonen, Van Dien Nguyen, You Zhou, Helena Vihinen, Eija Jokitalo, Gerhard Liebisch, P.A. Nidhina Haridas, Vesa M. Olkkonen, Medicum, University of Helsinki, Department of Anatomy, Institute of Biotechnology, Electron Microscopy, and Biosciences

Subjects
EXPRESSION, Carcinoma, Hepatocellular, hexosylceramide, INVASION, PROTEIN, Ceramides, Biochemistry, Phosphates, Endocrinology, mitochondrial function, Sphingosine, Golgi, EPIDEMIOLOGY, Humans, TANDEM MASS-SPECTROMETRY, RNA, Small Interfering, LIPID EXTRACTION, Cell Proliferation, Sphingolipids, glycosphingolipid, GOLPH2, CERAMIDE, HEPATOCELLULAR-CARCINOMA CELLS, Phosphatidylethanolamines, Cell Cycle, Liver Neoplasms, PROLIFERATION, Membrane Proteins, Cell Biology, Lipid Metabolism, dihexosylceramide, phosphatidylethanolamine, cholesteryl ester, &nbsp, 1182 Biochemistry, cell and molecular biology, 3111 Biomedicine, Cholesterol Esters, GP73
Abstract

Golgi membrane protein 1 (GOLM1) is a Golgi-resident type 2 transmembrane protein known to be overexpressed in several cancers, including he-patocellular carcinoma (HCC), as well as in viral in-fections. However, the role of GOLM1 in lipid metabolism remains enigmatic. In this study, we employed siRNA-mediated GOLM1 depletion in Huh -7 HCC cells to study the role of GOLM1 in lipid metabolism. Mass spectrometric lipidomic analysis in GOLM1 knockdown cells showed an aberrant accu-mulation of sphingolipids, such as ceramides, hex-osylceramides, dihexosylceramides, sphinganine, sphingosine, and ceramide phosphate, along with cholesteryl esters. Furthermore, we observed a reduction in phosphatidylethanolamines and lyso-phosphatidylethanolamines. In addition, Seahorse extracellular flux analysis indicated a reduction in mitochondrial oxygen consumption rate upon GOLM1 depletion. Finally, alterations in Golgi struc-ture and distribution were observed both by electron microscopy imaging and immunofluorescence mi-croscopy analysis. Importantly, we found that GOLM1 depletion also affected cell proliferation and cell cycle progression in Huh-7 HCC cells. The Golgi structural defects induced by GOLM1 reduction might potentially affect the trafficking of proteins and lipids leading to distorted intracellular lipid ho-meostasis, which may result in organelle dysfunction and altered cell growth. In conclusion, we demon-strate that GOLM1 depletion affects sphingolipid metabolism, mitochondrial function, Golgi structure, and proliferation of HCC cells.

Published
2022

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