Gene cascade analysis in human granulosa tumor cells (KGN) following exposure to high levels of free fatty acids and insulin. 2021

Patricia G Tremblay, and Chloé Fortin, and Marc-André Sirard
Centre de Recherche en Reproduction, Développement et Santé Intergénérationnelle, Faculté des Sciences de l'Agriculture et de l'Alimentation, Département des Sciences Animales, Université Laval, Québec, QC, G1V 0A6, Canada.

Maternal metabolic disorders such as obesity and diabetes are detrimental factors that compromise fertility and the success rates of medically assisted procreation procedures. During metabolic stress, adipose tissue is more likely to release free fatty acids (FFA) in the serum resulting in an increase of FFA levels not only in blood, but also in follicular fluid (FF). In humans, high concentrations of palmitic acid and stearic acid reduced granulosa cell survival and were associated with poor cumulus-oocyte complex (COC) morphology. Obesity and high levels of circulating FFA were also causatively linked to hampered insulin sensitivity in cells and compensatory hyperinsulinemia. To provide a global picture of the principal upstream signaling pathways and genomic mechanisms involved in this metabolic context, human granulosa-like tumor cells (KGN) were treated with a combination of palmitic acid, oleic acid, and stearic acid at the higher physiological concentrations found in the follicular fluid of women with a higher body mass index (BMI) (≥ 30.0 kg/m2). We also tested a high concentration of insulin alone and in combination with high concentrations of fatty acids. Transcription analysis by RNA-seq with a cut off for fold change of 1.5 and p-value 0.05 resulted in thousands of differentially expressed genes for each treatment. Using analysis software such as Ingenuity Pathway Analysis (IPA), we were able to establish that high concentrations of FFA affected the expression of genes mainly related to glucose and insulin homoeostasis, fatty acid metabolism, as well as steroidogenesis and granulosa cell differentiation processes. The combination of insulin and high concentrations of FFA affected signaling pathways related to apoptosis, inflammation, and oxidative stress. Taken together, our results provided new information on the mechanisms that might be involved in human granulosa cells exposed to high concentrations of FFA and insulin in the contexts of metabolism disorders.

UI MeSH Term Description Entries
D007249 Inflammation A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. Innate Inflammatory Response,Inflammations,Inflammatory Response, Innate,Innate Inflammatory Responses
D007328 Insulin A 51-amino acid pancreatic hormone that plays a major role in the regulation of glucose metabolism, directly by suppressing endogenous glucose production (GLYCOGENOLYSIS; GLUCONEOGENESIS) and indirectly by suppressing GLUCAGON secretion and LIPOLYSIS. Native insulin is a globular protein comprised of a zinc-coordinated hexamer. Each insulin monomer containing two chains, A (21 residues) and B (30 residues), linked by two disulfide bonds. Insulin is used as a drug to control insulin-dependent diabetes mellitus (DIABETES MELLITUS, TYPE 1). Iletin,Insulin A Chain,Insulin B Chain,Insulin, Regular,Novolin,Sodium Insulin,Soluble Insulin,Chain, Insulin B,Insulin, Sodium,Insulin, Soluble,Regular Insulin
D008928 Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed) Mitochondrial Contraction,Mitochondrion,Contraction, Mitochondrial,Contractions, Mitochondrial,Mitochondrial Contractions
D004734 Energy Metabolism The chemical reactions involved in the production and utilization of various forms of energy in cells. Bioenergetics,Energy Expenditure,Bioenergetic,Energy Expenditures,Energy Metabolisms,Expenditure, Energy,Expenditures, Energy,Metabolism, Energy,Metabolisms, Energy
D005230 Fatty Acids, Nonesterified FATTY ACIDS found in the plasma that are complexed with SERUM ALBUMIN for transport. These fatty acids are not in glycerol ester form. Fatty Acids, Free,Free Fatty Acid,Free Fatty Acids,NEFA,Acid, Free Fatty,Acids, Free Fatty,Acids, Nonesterified Fatty,Fatty Acid, Free,Nonesterified Fatty Acids
D005260 Female Females
D006106 Granulosa Cell Tumor A neoplasm composed entirely of GRANULOSA CELLS, occurring mostly in the OVARY. In the adult form, it may contain some THECA CELLS. This tumor often produces ESTRADIOL and INHIBIN. The excess estrogen exposure can lead to other malignancies in women and PRECOCIOUS PUBERTY in girls. In rare cases, granulosa cell tumors have been identified in the TESTES. Cancer of Granulosa Cells,Granulosa Cell Cancer,Cancer, Granulosa Cell,Cancers, Granulosa Cell,Cell Cancer, Granulosa,Cell Cancers, Granulosa,Cells Cancer, Granulosa,Cells Cancers, Granulosa,Granulosa Cell Cancers,Granulosa Cell Tumors,Granulosa Cells Cancer,Granulosa Cells Cancers,Tumor, Granulosa Cell,Tumors, Granulosa Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D015972 Gene Expression Regulation, Neoplastic Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in neoplastic tissue. Neoplastic Gene Expression Regulation,Regulation of Gene Expression, Neoplastic,Regulation, Gene Expression, Neoplastic
D017209 Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, i.e., DNA FRAGMENTATION. It is genetically programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Apoptosis, Extrinsic Pathway,Apoptosis, Intrinsic Pathway,Caspase-Dependent Apoptosis,Classic Apoptosis,Classical Apoptosis,Programmed Cell Death,Programmed Cell Death, Type I,Apoptoses, Extrinsic Pathway,Apoptoses, Intrinsic Pathway,Apoptosis, Caspase-Dependent,Apoptosis, Classic,Apoptosis, Classical,Caspase Dependent Apoptosis,Cell Death, Programmed,Classic Apoptoses,Extrinsic Pathway Apoptoses,Extrinsic Pathway Apoptosis,Intrinsic Pathway Apoptoses,Intrinsic Pathway Apoptosis

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