Hematopoietic upstream stimulating factor 1 deficiency is associated with increased atherosclerosis susceptibility in LDL receptor knockout mice

Total body upstream stimulatory factor 1 (USF1) deficiency in mice is associated with brown adipose tissue activation and a marked protection against the development of obesity and atherosclerotic lesions. Functional expression of USF1 has also been detected in monocytes and monocyte-derived macrophages. In the current study we therefore tested whether selective hematopoietic USF1 deficiency can also beneficially impact the development of atherosclerosis. For this purpose, LDL receptor knockout mice were transplanted with bone marrow from USF1 knockout mice or their wild-type littermate controls and subsequently fed a Western-type diet for 20 weeks to stimulate atherosclerotic lesion development. Strikingly, absence of USF1 function in bone marrow-derived cells was associated with exacerbated blood leukocyte (+ 100%; P < 0.01) and peritoneal leukocyte (+ 50%; P < 0.05) lipid loading and an increased atherosclerosis susceptibility (+ 31%; P < 0.05). These effects could be attributed to aggravated hyperlipidemia, i.e. higher plasma free cholesterol (+ 33%; P < 0.001) and cholesteryl esters (+ 39%; P < 0.001), and the development of hepatosteatosis. In conclusion, we have shown that hematopoietic USF1 deficiency is associated with an increased atherosclerosis susceptibility in LDL receptor knockout mice. These findings argue against a contribution of macrophage-specific USF1 deficiency to the previously described beneficial effect of total body USF1 deficiency on atherosclerosis susceptibility in mice.Peer reviewe

Acute central neuropeptide Y administration increases food intake but does not affect hepatic very low-density lipoprotein (VLDL) production in mice

Central neuropeptide Y (NPY) administration stimulates food intake in rodents. In addition, acute modulation of central NPY signaling increases hepatic production of very low-density lipoprotein (VLDL)-triglyceride (TG) in rats. As hypertriglyceridemia is an important risk factor for atherosclerosis, for which well-established mouse models are available, we set out to validate the effect of NPY on hepatic VLDL-TG production in mice, to ultimately investigate whether NPY, by increasing VLDL production, contributes to the development of atherosclerosis. Male C57Bl/6J mice received an intracerebroventricular (i.c.v.) cannula into the lateral (LV) or third (3V) ventricle of the brain. One week later, after a 4 h fast, the animals received an intravenous (i.v.) injection of Tran(35)S (100 µCi) followed by tyloxapol (500 mg/kg body weight; BW), enabling the study of hepatic VLDL-apoB and VLDL-TG production, respectively. Immediately after the i.v. injection of tyloxapol, the animals received either an i.c.v. injection of NPY (0.2 mg/kg BW in artificial cerebrospinal fluid; aCSF), synthetic Y1 receptor antagonist GR231118 (0.5 mg/kg BW in aCSF) or vehicle (aCSF), or an i.v. injection of PYY3-36 (0.5 mg/kg BW in PBS) or vehicle (PBS). Administration of NPY into both the LV and 3V increased food intake within one hour after injection (+164%, p <0.001 and +367%, p <0.001, respectively). NPY administration neither in the LV nor in the 3V affected hepatic VLDL-TG or VLDL-apoB production. Likewise, antagonizing central NPY signaling by either PYY3-36 or GR231118 administration did not affect hepatic VLDL production. In mice, as opposed to rats, acute central administration of NPY increases food intake without affecting hepatic VLDL production. These results are of great significance when extrapolating findings on the central regulation of hepatic VLDL production between specie

NPY administration into the third ventricle acutely increases food intake.

<p>NPY (0.2 mg/kg) was administered in the third ventricle under light isoflurane anaesthesia, and food intake was measured for two hours, starting at 09∶00 a.m. All animals served as their own controls (basal food intake). Values are means ± SD (n = 11), *<i>p</i><0.05, ***<i>p</i><0.001 compared to basal.</p

Stimulatory effect of insulin on glucose uptake by muscle involves the central nervous system in insulin-sensitive mice

Insulin inhibits endogenous glucose production (EGP) and stimulates glucose uptake in peripheral tissues. Hypothalamic insulin signaling is required for the inhibitory effects of insulin on EGP. We examined the contribution of central insulin signaling on circulating insulin-stimulated tissue-specific glucose uptake. Tolbutamide, an inhibitor of ATP-sensitive K(+) channels (K(ATP) channels), or vehicle was infused into the lateral ventricle in the basal state and during hyperinsulinemic-euglycemic conditions in postabsorptive, chow-fed C57Bl/6J mice and in postabsorptive C57Bl/6J mice with diet-induced obesity. Whole-body glucose uptake was measured by d-[(14)C]glucose kinetics and tissue-specific glucose uptake by 2-deoxy-d-[(3)H]glucose uptake. During clamp conditions, intracerebroventricular administration of tolbutamide impaired the ability of insulin to inhibit EGP by ∼20%. In addition, intracerebroventricular tolbutamide diminished insulin-stimulated glucose uptake in muscle (by ∼59%) but not in heart or adipose tissue. In contrast, in insulin-resistant mice with diet-induced obesity, intracerebroventricular tolbutamide did not alter the effects of insulin during clamp conditions on EGP or glucose uptake by muscle. Insulin stimulates glucose uptake in muscle in part through effects via K(ATP) channels in the central nervous system, in analogy with the inhibitory effects of insulin on EGP. High-fat diet-induced obesity abolished the central effects of insulin on liver and muscle. These observations stress the role of central insulin resistance in the pathophysiology of diet-induced insulin resistanc

NPY administration into the lateral ventricle acutely increases food intake.

<p>NPY (0.2 mg/kg) was administered in the left lateral ventricle under light isoflurane anaesthesia, and food intake was measured for two hours, starting at 09∶00 a.m. All animals served as their own controls (basal food intake). Values are means ± SD (n = 9), ***<i>p</i><0.001 compared to basal.</p

Corrigendum to “Proteoglycan 4 regulates macrophage function without altering atherosclerotic lesion formation in a murine bone marrow-specific deletion model.” [Atherosclerosis 274 (July 2018) 120–127]

The purpose of this research was to establish whether the implementation of adequate internal control procedures will enhance the financial management of tourist services MSEs in Lima, taking into account that the critical point for any losses caused by various factors, refer to absence of proper supervision of the implementation of internal control in the collection, influencing so many times in total liquidity. The research design was non-experimental, correlational with mixed approach (qualitative and quantitative), regarded as applied research because of the practical scope, applications underpinned by standards and technical tools of information gathering. We used a sample of 44 people involved in the conduct of business for services performed for different customers in general and companies accounted for 11 representative, who answered a questionnaire designed for the diagnosis, formulation and revision of strategies. The results and analysis of the research showed that there is an adequate internal control partially impossible, the fulfillment of the main objectives of all MSEs are immersed in this field.El propósito de la presente investigación fue establecer si la adecuada implementación de los procedimientos de control interno optimizará la gestión financiera en las Mypes de servicios turísticos en Lima Metropolitana, teniendo en cuenta que el punto crítico de las pérdidas ocasionadas por diversos factores, se refieren a la inexistencia de una la correcta supervisión de la implementación del control interno en las cobranzas, influyendo muchas veces en forma total en su liquidez. El diseño de la investigación fue de tipo no experimental, correlacional con enfoque mixto (cualitativo-cuantitativo), considerada como investigación aplicada, debido a los alcances prácticos, aplicativos sustentada por normas e instrumentos técnicos de recopilación de información. Se utilizó una muestra compuesta por 44 personas, involucradas en el desarrollo de las labores de servicios realizados a diversos clientes en general y que correspondió a 12 empresas representativas, quienes respondieron un cuestionario diseñado para el diagnóstico, formulación y revisión de estrategias. Los resultados y el análisis de la investigación demostraron que existe un inadecuado control interno que imposibilita de forma parcial, el cumplimiento de los objetivos principales de toda Mype inmersa en este rubro

NPY administration into the lateral ventricle does not affect hepatic VLDL production in anesthetized mice.

<p>After a 4 hour fast, mice were fully anesthetized and hepatic VLDL production was assessed. Mice received an i.v. injection of Tran³⁵S label (t = −30 min), followed by an injection of tyloxapol (t = 0 min), directly followed by an LV injection of NPY (0.2 mg/kg BW) or artificial cerebrospinal fluid (control). Plasma triglyceride (TG) levels were determined at indicated time points (A). VLDL-TG production rate was calculated from the slopes of the individual TG-time graphs (B). At t = 120 min, mice were exsanguinated and VLDL fractions were isolated from serum by ultracentrifugation. ³⁵S-apoB production was determined by scintillation counting of the isolated VLDL fraction (C). Values are means ± SD (n = 8−10).</p

NPY administration into the third ventricle does not affect hepatic VLDL production in conscious mice.

<p>Hepatic VLDL production was assessed after a 4h-fast. Mice received an i.v. injection of Tran³⁵S label (t = −30 min), followed by an injection of tyloxapol (t = 0 min), directly followed by a 3V injection of NPY (0.2 mg/kg BW) or artificial cerebrospinal fluid (control). Plasma triglyceride (TG) levels were determined at indicated time points (A). VLDL-TG production rate was calculated from the slopes of the individual TG-time graphs (B). At t = 120 min, mice were exsanguinated and VLDL fractions were isolated from serum by ultracentrifugation. ³⁵S-apoB production was determined by scintillation counting of the isolated VLDL fraction (C). Values are means ± SD (n = 9−12).</p

Corrigendum to: Proteoglycan 4 regulates macrophage function without altering atherosclerotic lesion formation in a murine bone marrow-specific deletion model (vol 274, pg 120, 2018)

Biopharmaceutic

Proteoglycan 4 regulates macrophage function without altering atherosclerotic lesion formation in a murine bone marrow-specific deletion model

Background and aims: Proteoglycan 4 (Prg4) has a high structural similarity with the established atherosclerosis-modulating proteoglycan versican, but its role in atherogenesis is still unknown. Therefore, the impact of Prg4 deficiency on macrophage function in vitro and atherosclerosis susceptibility in vivo was investigated. Methods: The presence and localization of Prg4 was studied in atherosclerotic lesions. Furthermore, the effect of Prg4 deficiency on macrophage foam cell formation, cholesterol efflux and lipopolysaccharide (LPS) response was determined. Finally, susceptibility for atherosclerotic lesion formation was investigated in bone marrow-specific Prg4 knockout (KO) mice. Results: Prg4 mRNA expression was induced 91-fold (p<0.001) in murine initial atherosclerotic lesions and Prg4 protein co-localized with human lesional macrophages. Murine Prg4 KO macrophages showed increased foam cell formation (+2.1-fold, p<0.01). In parallel, the expression of the cholesterol efflux genes ATP-binding cassette transporter A1 and scavenger receptor type B1 was lower (−35%, p<0.05;-40%, p<0.05) in Prg4 KO macrophages. This translated into an impaired cholesterol efflux to high-density lipoprotein (−13%, p<0.001) and apolipoprotein A1 (−8%, p<0.05). Furthermore, Prg4 KO macrophages showed an impaired LPS-induced rise in TNFα secretion as compared to wild-type controls (−31%, p<0.001), indicating a reduced inflammatory response. Combined, these pro- and anti-atherogenic effects did not translate into a significant difference in atherosclerotic lesion formation upon bone marrow-specific deletion of Prg4 in low-density lipoprotein receptor KO mice. Conclusions: Prg4 is present in macrophages in both murine and human atherosclerotic lesions and critically influences macrophage function, but deletion of Prg4 in bone marrow-derived cells does not affect atherosclerotic lesion development