Enhanced insulin sensitivity associated with provision of mono and polyunsaturated fatty acids in skeletal muscle cells involves counter modulation of PP2A

International audienceAims/Hypothesis: Reduced skeletal muscle insulin sensitivity is a feature associated with sustained exposure to excess saturated fatty acids (SFA), whereas mono and polyunsaturated fatty acids (MUFA and PUFA) not only improve insulin sensitivity but blunt SFA-induced insulin resistance. The mechanisms by which MUFAs and PUFAs institute these favourable changes remain unclear, but may involve stimulating insulin signalling by counter-modulation/repression of protein phosphatase 2A (PP2A). This study investigated the effects of oleic acid (OA; a MUFA), linoleic acid (LOA; a PUFA) and palmitate (PA; a SFA) in cultured myotubes and determined whether changes in insulin signalling can be attributed to PP2A regulation. Principal Findings: We treated cultured skeletal myotubes with unsaturated and saturated fatty acids and evaluated insulin signalling, phosphorylation and methylation status of the catalytic subunit of PP2A. Unlike PA, sustained incubation of rat or human myotubes with OA or LOA significantly enhanced Akt-and ERK1/2-directed insulin signalling. This was not due to heightened upstream IRS1 or PI3K signalling nor to changes in expression of proteins involved in proximal insulin signalling, but was associated with reduced dephosphorylation/inactivation of Akt and ERK1/2. Consistent with this, PA reduced PP2Ac demethylation and tyrosine 307 phosphorylation-events associated with PP2A activation. In contrast, OA and LOA strongly opposed these PA-induced changes in PP2Ac thus exerting a repressive effect on PP2A.Conclusions/Interpretation: Beneficial gains in insulin sensitivity and the ability of unsaturated fatty acids to oppose palmitate-induced insulin resistance in muscle cells may partly be accounted for by counter-modulation of PP2A

SIRT1 disruption in human fetal hepatocytes leads to increased accumulation of glucose and lipids

There are unprecedented epidemics of obesity, such as type II diabetes and non-alcoholic fatty liver diseases (NAFLD) in developed countries. A concerning percentage of American children are being affected by obesity and NAFLD. Studies have suggested that the maternal environment in utero might play a role in the development of these diseases later in life. In this study, we documented that inhibiting SIRT1 signaling in human fetal hepatocytes rapidly led to an increase in intracellular glucose and lipids levels. More importantly, both de novo lipogenesis and gluconeogenesis related genes were upregulated upon SIRT1 inhibition. The AKT/FOXO1 pathway, a major negative regulator of gluconeogenesis, was decreased in the human fetal hepatocytes inhibited for SIRT1, consistent with the higher level of gluconeogenesis. These results indicate that SIRT1 is an important regulator of lipid and carbohydrate metabolisms within human fetal hepatocytes, acting as an adaptive transcriptional response to environmental changes

Sobrevivencia de pacientes con Enfermedad Renal Crónica Tradicional y no Tradicional en clínicas de hemodiálisis del Instituto Guatemalteco de Seguridad Social de Escuintla, Suchitepéquez y Retalhuleu, Guatemala

A nivel mundial, la enfermedad renal crónica (ERC), representa un problema de salud ingente, con un incremento de 82.3 % de muertes en las últimas dos décadas, ya sea por la ERC secundaria a diabetes o hipertensión arterial entre otras, o la enfermedadrenal crónica de causa no tradicional (ERCnT), relacionada con las condiciones extremas de trabajo agrícola en Mesoamérica, la inadecuada rehidratación y al estrés por calor. Debido a la falta de datos sobre las características epidemiológicas de estasenfermedades, se realizó un estudio sobre la sobrevivencia de 55 pacientes con ERC y ERCnT, en tres departamentos de la costa sur de Guatemala, por medio de un estudio transversal retrospectivo en pacientes en estadio V con tratamiento de hemodiálisisen el Instituto Guatemalteco de Seguridad Social (IGSS). Se aplicó el análisis estadístico de Kaplan-Meier para calcular las tasas de sobrevivencia a 5 años. Se determinó que la ERCnT tiene una mayor sobrevivencia (69.6 %) con respecto a ERC (38.9 %) yuna mayor tasa de sobrevivencia en mujeres (58.8 %) que en hombres (47.4 %). Al comparar las vías de acceso vascular en la hemodiálisis, los pacientes con fístula tienen menor tasa de mortalidad (22.9) que los que utilizaban catéter (39.0). La tasa de incidencia de mortalidad general en pacientes con ERC y ERCnT durante el período de enero de 2013 a agosto 2019 fue de 29.1 por 100 años/personas. La mayor tasa de mortalidad en estos pacientes estuvo asociada a eventos cardiovasculares (36.4 %)

Sobrevivencia de pacientes con Enfermedad Renal Crónica Tradicional y no Tradicional en clínicas de hemodiálisis del Instituto Guatemalteco de Seguridad Social de Escuintla, Suchitepéquez y Retalhuleu, Guatemala

A nivel mundial, la enfermedad renal crónica (ERC), representa un problema de salud ingente, con un incremento de 82.3 % de muertes en las últimas dos décadas, ya sea por la ERC secundaria a diabetes o hipertensión arterial entre otras, o la enfermedadrenal crónica de causa no tradicional (ERCnT), relacionada con las condiciones extremas de trabajo agrícola en Mesoamérica, la inadecuada rehidratación y al estrés por calor. Debido a la falta de datos sobre las características epidemiológicas de estasenfermedades, se realizó un estudio sobre la sobrevivencia de 55 pacientes con ERC y ERCnT, en tres departamentos de la costa sur de Guatemala, por medio de un estudio transversal retrospectivo en pacientes en estadio V con tratamiento de hemodiálisisen el Instituto Guatemalteco de Seguridad Social (IGSS). Se aplicó el análisis estadístico de Kaplan-Meier para calcular las tasas de sobrevivencia a 5 años. Se determinó que la ERCnT tiene una mayor sobrevivencia (69.6 %) con respecto a ERC (38.9 %) yuna mayor tasa de sobrevivencia en mujeres (58.8 %) que en hombres (47.4 %). Al comparar las vías de acceso vascular en la hemodiálisis, los pacientes con fístula tienen menor tasa de mortalidad (22.9) que los que utilizaban catéter (39.0). La tasa de incidencia de mortalidad general en pacientes con ERC y ERCnT durante el período de enero de 2013 a agosto 2019 fue de 29.1 por 100 años/personas. La mayor tasa de mortalidad en estos pacientes estuvo asociada a eventos cardiovasculares (36.4 %)

Oxidation of DJ-1 Induced by 6-Hydroxydopamine Decreasing Intracellular Glutathione

DJ-1, the causative gene of a familial form of Parkinson's disease (PD), has been reported to undergo preferential oxidation of the cysteine residue at position 106 (Cys-106) under oxidative stress; however, details of the molecular mechanisms are not well known. In the present study, mechanisms of DJ-1 oxidation induced by 6-hydroxydopamine (6-OHDA) were investigated by using SH-SY5Y cells. The treatment of these cells with 6-OHDA caused an obvious acidic spot sift of DJ-1 due to its oxidation. However, when catalase, which is an hydrogen peroxide (H2O2)-removing enzyme, was added during the treatment, it failed to prevent the oxidation induced by 6-OHDA, suggesting that electrophilic p-quinone formed from 6-OHDA, but not H2O2, was responsible for the DJ-1 oxidation. Benzoquinone, another electrophilic p-quinone, also induced DJ-1 oxidation. The intracellular glutathione (GSH) levels were significantly decreased by 6-OHDA, irrespective of the presence or absence of catalase. The inhibition of GSH synthesis by buthionine sulfoximine resulted in a decrease in GSH levels and enhancement of DJ-1 oxidation. The pretreatment of cells with N-acetyl-cysteine prevented the loss of intracellular GSH and subsequently DJ-1 oxidation induced by 6-OHDA. Collectively, these results suggest that electrophilic p-quinone formed from 6-OHDA induces DJ-1 oxidation by decreasing intracellular GSH

A secretome profile indicative of oleate-induced proliferation of HepG2 hepatocellular carcinoma cells

Increased fatty acid (FA) is often observed in highly proliferative tumors. FAs have been shown to modulate the secretion of proteins from tumor cells, contributing to tumor survival. However, the secreted factors affected by FA have not been systematically explored. Here, we found that treatment of oleate, a monounsaturated omega-9 FA, promoted the proliferation of HepG2 cells. To examine the secreted factors associated with oleate-induced cell proliferation, we performed a comprehensive secretome profiling of oleate-treated and untreated HepG2 cells. A comparison of the secretomes identified 349 differentially secreted proteins (DSPs; 145 upregulated and 192 downregulated) in oleate-treated samples, compared to untreated samples. The functional enrichment and network analyses of the DSPs revealed that the 145 upregulated secreted proteins by oleate treatment were mainly associated with cell proliferation-related processes, such as lipid metabolism, inflammatory response, and ER stress. Based on the network models of the DSPs, we selected six DSPs (MIF, THBS1, PDIA3, APOA1, FASN, and EEF2) that can represent such processes related to cell proliferation. Thus, our results provided a secretome profile indicative of an oleate-induced proliferation of HepG2 cell