The Significance of Lipoproteins in the Development of Obesity.

Disruption of lipoprotein metabolism plays an important role in the development of several cardiovascular, inflammatory, and metabolic diseases. This review examines the importance of different types of lipoproteins and the role they play in the development of dyslipidemia in obesity. The causes and consequences associated with the disruption of lipid metabolism and its significance in the pathogenesis of obesity are considered. The relationship between such pathological processes, which occur alongside obesity as dyslipidemia and inflammation, is determined. In view of the current efficacy and toxicity limitations of currently approved drugs, natural compounds as potential therapeutic agents in the treatment of obesity are considered in the review. The complex mechanisms of lipid metabolism normalization in obesity found for these compounds can serve as one of the confirmations of their potential efficacy in treating obesity. Nanoparticles can serve as carriers for the considered drugs, which can improve their pharmacokinetic properties.

Effect of quercetin administration during the first two weeks post-weaning on the development of non-alcoholic fatty liver disease and dyslipidaemia in Sprague Dawley rats fed a high fructose diet.

Hepatic steatosis and dyslipidaemia are associated with excessive fructose consumption. We investigated the effect of quercetin intake during the early pre-weaning period on metabolic dysfunction caused by a high fructose diet. Sprague Dawley rats, 21-day-old, were weaned onto standard rat chow and randomly allocated to four groups which either water or 20% fructose solution to drink with or without quercetin (100 mg/kg body mass). Quercetin was administered for two weeks. Thereafter, rats continued on their respective diets for six weeks without quercetin. Terminally, serum triglyceride concentrations were not significantly different (p > 0.05) between males across groups. However, females receiving quercetin alone had lower serum triglyceride levels than those receiving fructose (p < 0.01). Quercetin increased the incidence of hepatic steatosis in female rats. Quercetin intake in the immediate post-weaning period may prevent hypertriglyceridemia. However, female rats receiving quercetin alone are predisposed to hepatic steatosis associated with a high fructose diet.

Consumo de fructosa y síndrome metabólico en pacientes adultos de un Hospital Militar / Fructose consumption and metabolic syndrome in adult patients of a military hospital

Introducción: La fructosa de la dieta se metaboliza a nivel hepático, en donde estimula la fructólisis, la glucólisis, la lipogénesis y la producción de glucosa, esto conlleva a la dislipidemia mixta, hiperglucemia e hígado graso; aumentando el riesgo de síndrome metabólico.Objetivo: Determinar la asociación entre el consumo de fructosa y síndrome metabólico en pacientes adultos atendidos en el Hospital Militar Central “Coronel Luis Arias Schreiber”.Materiales y Métodos: Investigación de enfoque cuantitativo, diseño no experimental, transversal, correlacional-causal. La población de estudio estuvo conformada por 75 pacientes adultos. Se incluyó pacientes mayores de 18 años de edad; quienes en forma voluntaria firmaron el consentimiento informado y presentaron registros actualizados de perfil bioquímico, fueron excluidos pacientes con discapacidad mental, motora y/o física. Los valores de presión arterial y perfil bioquímico; se obtuvo de las historias clínicas y la valoración antropométrica a través de la medición del peso corporal, talla y circunferencia abdominal; la ingesta de fructosa se obtuvo a través de un cuestionario de frecuencia de consumo semicuantitativo. Se utilizó la prueba estadística de Chi cuadrado para evaluar la asociación de variables.Resultados: El 61,3% presentó Síndrome Metabólico (SM), el 88% presentan un inadecuado consumo de fructosa (>25g/día). El índice de masa corporal (IMC) promedio fue de 30,34 (DE ±4,0); el nivel de glucosa en ayunas fue 100,13 mg/dL (DE ±11,25). Al asociar el consumo inadecuado de fructosa con el Síndrome Metabólico, se obtuvo un valor p= 0,010 (p<0,05). Asimismo, el consumo inadecuado de fructosa añadida tuvo asociación con el SM (p<0,05). No obstante, al asociar ingesta de fructosa natural con el SM, se obtuvo p =0.466 (p>0,05).(AU)

Introduction: Dietary fructose is metabolized in the liver,where it stimulates fructolysis, glycolysis, lipogenesis andglucose production, which leads to mixed dyslipidemia, hy-perglycemia and fatty liver; increasing the risk of metabolicsyndrome. Objetive: Determine the association between fructose con-sumption and metabolic syndrome in adult patients treated atthe “Coronel Luis Arias Schreiber” Central Military Hospital. Materials and methods: A quantitative approach studywas carried out, with a non-experimental, cross-sectional andcorrelational-causal design. The study population consisted of 75 adult patients. Patients over 18 years of age were in-cluded; who voluntarily signed the informed consent and pre-sented updated biochemical profile records. Patients withmental, motor and/or physical disabilities were excluded.Blood pressure and biochemical profile values were obtainedfrom medical records and anthropometric assessmentthrough measurement of body weight, height, and abdominalcircumference. Fructose intake was obtained through a semi-quantitative consumption frequency questionnaire. The Chisquare statistical test was used to evaluate the association ofvariables. Results: 61.3% presented Metabolic Syndrome (MS), 88%presented inadequate fructose consumption (>25g/day). Theaverage body mass index (BMI) was 30.34 (SD ±4.0); Thefasting glucose level was 100.13 mg/dL (SD ±11.25). Whenassociating inadequate fructose consumption with MetabolicSyndrome, a p value = 0.010 (p < 0.05) was obtained.Likewise, inadequate consumption of added fructose was as-sociated with MS (p<0.05). However, when associating natu-ral fructose intake with MS, p =0.466 (p>0.05) was obtained.Conclusions. A high consumption of added fructose in in-dustrialized foods has a greater association with the develop-ment of Metabolic Syndrome; It is necessary to reduce thefructose content in industrialized foods.(AU)

Beneficial Impact of Eicosapentaenoic Acid on the Adverse Effects Induced by Palmitate and Hyperglycemia on Healthy Rat Chondrocyte.

Osteoarthritis (OA) is the most prevalent form of arthritis and a major cause of pain and disability. The pathology of OA involves the whole joint in an inflammatory and degenerative process, especially in articular cartilage. OA may be divided into distinguishable phenotypes including one associated with the metabolic syndrome (MetS) of which dyslipidemia and hyperglycemia have been individually linked to OA. Since their combined role in OA pathogenesis remains to be elucidated, we investigated the chondrocyte response to these metabolic stresses, and determined whether a n-3 polyunsaturated fatty acid (PUFA), i.e., eicosapentaenoic acid (EPA), may preserve chondrocyte functions. Rat chondrocytes were cultured with palmitic acid (PA) and/or EPA in normal or high glucose conditions. The expression of genes encoding proteins found in cartilage matrix (type 2 collagen and aggrecan) or involved in degenerative (metalloproteinases, MMPs) or in inflammatory (cyclooxygenase-2, COX-2 and microsomal prostaglandin E synthase, mPGES) processes was analyzed by qPCR. Prostaglandin E2 (PGE2) release was also evaluated by an enzyme-linked immunosorbent assay. Our data indicated that PA dose-dependently up-regulated the mRNA expression of MMP-3 and -13. PA also induced the expression of COX-2 and mPGES and promoted the synthesis of PGE2. Glucose at high concentrations further increased the chondrocyte response to PA. Interestingly, EPA suppressed the inflammatory effects of PA and glucose, and strongly reduced MMP-13 expression. Among the free fatty acid receptors (FFARs), FFAR4 partly mediated the EPA effects and the activation of FFAR1 markedly reduced the inflammatory effects of PA in high glucose conditions. Our findings demonstrate that dyslipidemia associated with hyperglycemia may contribute to OA pathogenesis and explains why an excess of saturated fatty acids and a low level in n-3 PUFAs may disrupt cartilage homeostasis.

Gut ribotoxic stress responses facilitate dyslipidemia via metabolic reprogramming: an environmental health prediction.

Rationale: The gut and its accessory organ, the liver, are crucial determinants of metabolic homeostasis via the regulation of circulating lipids for cardiovascular health. In response to environmental insults, cells undergo diverse adaptation or pathophysiological processes via stress-responsive eukaryotic initiation factor 2 alpha (eIF2α) kinase signaling and subsequent cellular reprogramming. We noted that patients with inflammatory gut distress display enhanced levels of ribosomal stress-responsive eIF2α kinase, which is notably associated with lipid metabolic process genes. Based on an assumption that eukaryotic ribosomes are a promising stress-responsive module for molecular reprogramming, chemical ribosome-inactivating stressors (RIS) were assessed for their involvement in enterohepatic lipid regulation. Methods: Experimental assessment was based on prediction using the clinical transcriptome and single-cell RNA-sequencing analysis of inflammatory bowel diseases and obesity. The prediction was verified using RIS exposure models of mice, gut organoids, and intestinal cells. The lipidomic profiling was performed to address RIS-induced intracellular fat alterations. Biochemical processes of the mechanisms were evaluated using RT-PCR, western blot analysis, luciferase reporter assays, and confocal microscopy of genetically ablated or chemically inhibited mice, organoids, and cells. Results: Chemical RIS including deoxynivalenol promoted enterohepatic lipid sequestration while lowering blood LDL cholesterol in normal and diet-induced obese mice. Although ribosomal stress caused extensive alterations in cellular lipids and metabolic genes, the cholesterol import-associated pathway was notably modulated. In particular, ribosomal stress enhanced gut levels of the low-density lipoprotein receptor (LDLR) via both transcriptional and post-transcriptional regulation. Subsequently, LDLR facilitated enterohepatic cholesterol accumulation, leading to dyslipidemia in response to ribosomal stress. Moreover, genetic features of stress-responsive LDLR modulators were consistently proven in the inflammation- and obesity-associated gut model. Conclusion: The elucidated ribosome-linked gut lipid regulation provides predictive insights into stress-responsive metabolic rewiring in chronic human diseases as an environmental health prediction.

Deficiency of the lipid flippase ATP10A causes diet-induced dyslipidemia in female mice.

Genetic association studies have linked ATP10A and closely related type IV P-type ATPases (P4-ATPases) to insulin resistance and vascular complications, such as atherosclerosis. ATP10A translocates phosphatidylcholine and glucosylceramide across cell membranes, and these lipids or their metabolites play important roles in signal transduction pathways regulating metabolism. However, the influence of ATP10A on lipid metabolism in mice has not been explored. Here, we generated gene-specific Atp10A knockout mice and show that Atp10A-/- mice fed a high-fat diet did not gain excess weight relative to wild-type littermates. However, Atp10A-/- mice displayed female-specific dyslipidemia characterized by elevated plasma triglycerides, free fatty acids and cholesterol, as well as altered VLDL and HDL properties. We also observed increased circulating levels of several sphingolipid species along with reduced levels of eicosanoids and bile acids. The Atp10A-/- mice also displayed hepatic insulin resistance without perturbations to whole-body glucose homeostasis. Thus, ATP10A has a sex-specific role in regulating plasma lipid composition and maintaining hepatic liver insulin sensitivity in mice.

Deletion of Elovl5 leads to dyslipidemia and atherosclerosis in LDLR-deficient mice.

Atherosclerosis is a chronic inflammatory disease for which hepatic steatosis and atherogenic dyslipidemia are significant risk factors. We investigated the effects of endogenously generated very-long-chain polyunsaturated fatty acids (VL-PUFAs) on dyslipidemia and atherosclerosis development using mice that lack ELOVL5, a PUFA elongase that is required for the synthesis of arachidonic acid, EPA, and DHA from the essential fatty acids linoleic and linolenic acids, and the LDL receptor (LDLR). Elovl5-/-;Ldlr-/- mice manifest increased liver triglyceride and cholesterol concentrations due to the activation of sterol regulatory element binding protein-1, a transcription factor that activates enzymes required for de novo lipogenesis. Plasma levels of triglycerides and cholesterol in VLDL, IDL, and LDL were markedly elevated in Elovl5-/-;Ldlr-/- mice fed a chow and the mice exhibited marked aortic atherosclerotic plaques. Bone marrow-derived monocytes from wild-type (WT) and Elovl5-/- mice were polarized to M1 and M2 macrophages, and the effects of ELOVL5 on inflammatory activity were determined. There were no differences in most of the markers tested for M1 and M2 polarized cells between WT and Elovl5-/- cells, except for a slight increase in PGE2 secretion in Elovl5-/- cells, likely due to elevated Cox-2 expression. These results suggest that the deletion of Elovl5 leads to hepatic steatosis and dyslipidemia, which are the major factors in severe atherosclerosis in Elovl5-/-;Ldlr-/- mice.

Role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in diabetic complications.

Cardiovascular disease (CVD) complications have remained a major cause of death among patients with diabetes. Hence, there is a need for effective therapeutics against diabetes-induced CVD complications. Since its discovery, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been reported to be involved in the pathology of various CVDs, with studies showing a positive association between plasma levels of PCSK9, hyperglycemia, and dyslipidemia. PCSK9 regulates lipid homeostasis by interacting with low-density lipoprotein receptors (LDLRs) present in hepatocytes and subsequently induces LDLR degradation via receptor-mediated endocytosis, thereby reducing LDL uptake from circulation. In addition, PCSK9 also induces pro-inflammatory cytokine expression and apoptotic cell death in diabetic-CVD. Furthermore, therapies designed to inhibit PCSK9 effectively reduces diabetic dyslipidemia with clinical studies reporting reduced cardiovascular events in patients with diabetes and no significant adverse effect on glycemic controls. In this review, we discuss the role of PCSK9 in the pathogenesis of diabetes-induced CVD and the potential mechanisms by which PCSK9 inhibition reduces cardiovascular events in diabetic patients.

Administration of Linoleoylethanolamide Reduced Weight Gain, Dyslipidemia, and Inflammation Associated with High-Fat-Diet-Induced Obesity.

Acylethanolamides (NAEs) are bioactive lipids derived from diet fatty acids that modulate important homeostatic functions, including appetite, fatty acid synthesis, mitochondrial respiration, inflammation, and nociception. Among the naturally circulating NAEs, the pharmacology of those derived from either arachidonic acid (Anandamide), oleic acid (OEA), and palmitic acid (PEA) have been extensively characterized in diet-induced obesity. For the present work, we extended those studies to linoleoylethanolamide (LEA), one of the most abundant NAEs found not only in plasma and body tissues but also in foods such as cereals. In our initial study, circulating concentrations of LEA were found to be elevated in overweight humans (body mass index (BMI, Kg/m2) > 25) recruited from a representative population from the south of Spain, together with AEA and the endocannabinoid 2-Arachidonoyl glycerol (2-AG). In this population, LEA concentrations correlated with the circulating levels of cholesterol and triglycerides. In order to gain insight into the pharmacology of LEA, we administered it for 14 days (10 mg/kg i.p. daily) to obese male Sprague Dawley rats receiving a cafeteria diet or a standard chow diet for 12 consecutive weeks. LEA treatment resulted in weight loss and a reduction in circulating triglycerides, cholesterol, and inflammatory markers such as Il-6 and Tnf-alpha. In addition, LEA reduced plasma transaminases and enhanced acetyl-CoA-oxidase (Acox) and Uncoupling protein-2 (Ucp2) expression in the liver of the HFD-fed animals. Although the liver steatosis induced by the HFD was not reversed by LEA, the overall data suggest that LEA contributes to the homeostatic signals set in place in response to diet-induced obesity, potentially contributing with OEA to improve lipid metabolism after high fat intake. The anti-inflammatory response associated with its administration suggests its potential for use as a nutrient supplement in non-alcoholic steatohepatitis.

Perilipin 2-positive mononuclear phagocytes accumulate in the diabetic retina and promote PPARγ-dependent vasodegeneration.

Type 2 diabetes mellitus (T2DM), characterized by hyperglycemia and dyslipidemia, leads to nonproliferative diabetic retinopathy (NPDR). NPDR is associated with blood-retina barrier disruption, plasma exudates, microvascular degeneration, elevated inflammatory cytokine levels, and monocyte (Mo) infiltration. Whether and how the diabetes-associated changes in plasma lipid and carbohydrate levels modify Mo differentiation remains unknown. Here, we show that mononuclear phagocytes (MPs) in areas of vascular leakage in DR donor retinas expressed perilipin 2 (PLIN2), a marker of intracellular lipid load. Strong upregulation of PLIN2 was also observed when healthy donor Mos were treated with plasma from patients with T2DM or with palmitate concentrations typical of those found in T2DM plasma, but not under high-glucose conditions. PLIN2 expression correlated with the expression of other key genes involved in lipid metabolism (ACADVL, PDK4) and the DR biomarkers ANGPTL4 and CXCL8. Mechanistically, we show that lipid-exposed MPs induced capillary degeneration in ex vivo explants that was inhibited by pharmaceutical inhibition of PPARγ signaling. Our study reveals a mechanism linking dyslipidemia-induced MP polarization to the increased inflammatory cytokine levels and microvascular degeneration that characterize NPDR. This study provides comprehensive insights into the glycemia-independent activation of Mos in T2DM and identifies MP PPARγ as a target for inhibition of lipid-activated MPs in DR.

Effect of (poly)phenol-rich 'Daux Belan' apple supplementation on diet-induced obesity and glucose intolerance in C57BL/6NCrl mice.

Obesity is a state of metabolic dysfunction that can lead to dyslipidemia and impaired glucose homeostasis. Apple polyphenols have been shown to ameliorate dyslipidemia/metabolic dysfunction in humans. The influence of apple (poly)phenols on energy metabolism in high-fat (HF) diet-induced obese mice remains controversial. This study examined the effect of dietary supplementation of (poly)phenol-rich 'Daux Belan' apple (DB; 6.2 mg gallic acid equivalence (GAE)/mouse/day; 0.15% (poly)phenol) in the form of freeze-dried powder on glucose and lipid metabolism in male HF-fed C57BL/6NCrl mice, in comparison to low-(poly)phenol-containing 'Zestar' apple (Z; 0.4 mg GAE/mouse/day). Obesity, glucose intolerance, hypertriglyceridemia, and hepatic lipid vacuolation were induced by HF feeding while circulating cholesterol levels remained unchanged. DB apple supplementation did not protect against HF-induced body weight gain, hyperglycemia, hepatic triglyceride level elevation, and hepatic lipid vacuolation at the tested dosage. Future studies should be conducted with increased DB dosage and employ apple (poly)phenols supplemented in the form of extracts or sugar-free powder.

Lipolysis inhibition as a treatment of clinical ketosis in dairy cows: A randomized clinical trial.

Excessive and protracted lipolysis in adipose tissues of dairy cows is a major risk factor for clinical ketosis (CK). This metabolic disease is common in postpartum cows when lipolysis provides fatty acids as an energy substrate to offset negative energy balance. Lipolysis in cows can be induced by the canonical (hormonally induced) and inflammatory pathways. Current treatments for CK focus on improving glucose in blood (i.e., oral propylene glycol [PG], or i.v. dextrose). However, these therapies do not inhibit the canonical and inflammatory lipolytic pathways. Niacin (NIA) can reduce activation of the canonical pathway. Blocking inflammatory responses with cyclooxygenase inhibitors such as flunixin meglumine (FM) can inhibit inflammatory lipolytic activity. The objective of this study was to determine the effects of including NIA and FM in the standard PG treatment for postpartum CK on circulating concentrations of ketone bodies. A 4-group, parallel, individually randomized trial was conducted in multiparous Jersey cows (n = 80) from a commercial dairy in Michigan during a 7-mo period. Eligible cows had CK symptoms (lethargy, depressed appetite, and milk yield) and hyperketonemia (blood ß-hydroxybutyrate [BHB] ≥1.2 mmol/L). Cows with CK were randomly assigned to 1 of 3 groups where the first group received 310 g of oral PG once per day for 5 d; the second group received PG for 5 d + 24 g of oral NIA once per day for 3 d (PGNIA); and the third group received PG for 5 d + NIA for 3 d + 1.1 mg/kg i.v. FM once per day for 3 d (PGNIAFM). The control group consisted of cows that were clinically healthy (HC; untreated; BHB <1.2 mmol/L, n = 27) matching for parity and DIM with all 3 groups. Animals were sampled at enrollment (d 0), and d 3, 7, and 14 to evaluate ketone bodies and circulating metabolic and inflammatory biomarkers. Effects of treatment, sampling day, and their interactions were evaluated using mixed effects models. Logistic regression was used to calculate the odds ratio (OR) of returning to normoketonemia (BHB <1.2 mmol/L). Compared with HC, enrolled CK cows exhibited higher blood concentrations of dyslipidemia markers, including nonesterified fatty acids (NEFA) and BHB, and lower glucose and insulin levels. Cows with CK also had increased levels of biomarkers of pain (substance P), inflammation, including lipopolysaccharide-binding protein, haptoglobin, and serum amyloid A, and proinflammatory cytokines IL-4, MCP-1, MIP-1α, and TNFα. Importantly, 72.2% of CK cows presented endotoxemia and had higher circulating bacterial DNA compared with HC. By d 7, the percentage of cows with normoketonemia were higher in PGNIAFM = 87.5%, compared with PG = 58.33%, and PGNIA = 62.5%. At d 7 the OR for normoketonemia in PGNIAFM cows were 1.5 (95% CI, 1.03-2.17) and 1.4 (95% CI, 0.99-1.97) relative to PG and PGNIA, respectively. At d 3, 7, and 14, PGNIAFM cows presented the lowest values of BHB (PG = 1.36; PGNIA = 1.24; PGNIAFM = 0.89 ± 0.13 mmol/L), NEFA (PG = 0.58; PGNIA = 0.59; PGNIAFM = 0.45 ± 0.02 mmol/L), and acute phase proteins. Cows in PGNIAFM also presented the highest blood glucose increment across time points and insulin by d 7. These data provide evidence that bacteremia or endotoxemia, systemic inflammation, and pain may play a crucial role in CK pathogenesis. Additionally, targeting lipolysis and inflammation with NIA and FM during CK effectively reduces dyslipidemia biomarkers, improves glycemia, and improves overall clinical recovery.

Dyslipidemia initiates keratinocytes proliferation through upregulation of lncRNA NEAT in psoriasis patients.

BACKGROUND: Psoriasis is a chronic inflammatory immune-mediated and hyper proliferative skin disorder that has underlying genetic factors. Psoriasis can result from interaction of cytokines between keratinocytes and T-lymphocytes. NEAT is a lncRNA involved in immune modulation and has been previously studied in cancers. This study aims to clarify the unprecedented role of NEAT in psoriasis pathogenesis. METHODS: The study was conducted on 50 healthy control subjects and 50 psoriasis patients. Blood samples from all participants were collected for analysis of their lipid profile. qRT-PCR was done for lncRNA NEAT, TNF-α, VEGF genes expression. The levels of ROS and caspase-3 were estimated by ELISA. ROC analysis was done to detect the diagnostic value of lncRNA NEAT gene expression. RESULTS: Dyslipidemia is more prevalent among psoriasis patients. A significant up regulation in lncRNA NEAT, TNF-α, VEGF genes expression (p value˂0.001) in psoriasis patients in addition to significant increase in ROS and caspase-3 levels (p value˂0.001) in compare to controls. Additionally, a positive significant correlation between TNF-α, ROS, NEAT, caspase-3 and dyslipidemia. NEAT had an area under the curve (AUC) of 0.931 (95% CI 0.844-0.978, p < 0.001). CONCLUSION: Dyslipidemia is an initiating signal in psoriasis pathogenesis that creates a state of chronic inflammation and oxidative stress. This state induces keratinocytes proliferation and release of NEAT with subsequent caspase-3 activation to counteract the proliferating cells. NEAT could be considered as a good diagnostic biomarker for psoriasis.

Association of circulatory PCSK-9 with biomarkers of redox imbalance and inflammatory cascades in the prognosis of diabetes and associated complications: a pilot study in the Indian population.

AbstractsBesides the profound role of proprotein convertase subtilisin/kexin type-9 (PCSK-9) in LDL-C regulation, its association with other metabolic complications cannot be disregarded. The co-existence of redox imbalance and inflammatory cascades has greatly reflected the etiology of hyperglycemia. Therefore, we studied the association of PCSK-9 with inflammation and oxidative stress biomarkers to predict its role in the prognosis of diabetes and its associated complications in the Indian population. This pilot study examined a total of n = 187 subjects: healthy controls (HC; n = 50), diabetic without complication (T2DM; n = 49), diabetic nephropathy (T2DM-N; n = 43), and diabetic dyslipidemic (T2DM-DL; n = 45) subjects. The relationship between circulatory PCSK-9 levels and inflammation and redox imbalance biomarkers has been explored. The significant positive association of elevated PCSK-9 level with the inflammatory (i.e. IL-1ß, IL-6, TNF-α, and CRP) and oxidative stress marker (i.e. XOD, CD, LOOH, and MDA) was observed in T2DM-N and T2DM-DL subjects. Whereas single regression analysis depicted that PCSK-9 was inversely associated with the FRAP and PON-1 in T2DM-N and T2DM-DL subjects. Furthermore, no significant correlation was detected in both T2DM and HC subjects. We found a significant relationship between these prognostic biomarkers with an elevated level of PCSK-9 in T2DM-N and T2DM-DL subjects. PCSK-9 is a nontraditional biomarker in diabetes that may help identify patients at risk of developing secondary complications of diabetes in the Indian population. However, further large cohort validation studies are needed.

Fat distribution measurements by chemical shift-encoded transition region extraction predict the risk of hyperglycaemia, dyslipidaemia and metabolic syndrome in mice.

Metabolically healthy or unhealthy obesity is closely related to metabolic syndrome (MetS). To validate a more accurate diagnostic method for obesity that reflects the risk of metabolic disorders in a pre-clinical mouse model, C57BL/6J mice were fed high-sucrose-high-fat and chow diets for 12 weeks to induce obesity. MRI was performed and analysed by chemical shift-encoded fat-water separation based on the transition region extraction method. Abdominal fat was divided into upper and lower abdominal regions at the horizontal lower border of the liver. Blood samples were collected, and the glucose level, lipid profile, liver function, HbA1c and insulin were tested. k-means clustering and stepwise logistic regression were applied to validate the diagnosis of hyperglycaemia, dyslipidaemia and MetS, and to ascertain the predictive effect of MRI-derived parameters to the metabolic disorders. Pearson or Spearman correlation was used to assess the relationship between MRI-derived parameters and metabolic traits. The receiver-operating characteristic curve was used to evaluate the diagnostic effect of each logistic regression model. A two-sided p value less than 0.05 was considered to indicate statistical significance for all tests. We made the precise diagnosis of obesity, dyslipidaemia, hyperglycaemia and MetS in mice. In all, 14 mice could be diagnosed as having MetS, and the levels of body weight, HbA1c, triglyceride, total cholesterol and low-density lipoprotein cholesterol were significantly higher than in the normal group. Upper abdominal fat better predicted dyslipidaemia (odds ratio, OR = 2.673; area under the receiver-operating characteristic curve, AUCROC = 0.9153) and hyperglycaemia (OR = 2.456; AUCROC = 0.9454), and the abdominal visceral adipose tissue (VAT) was better for predicting MetS risk (OR = 1.187; AUCROC = 0.9619). We identified the predictive effect of fat volume and distribution in dyslipidaemia, hyperglycaemia and MetS. The upper abdominal fat played a better predictive role for the risk of dyslipidaemia and hyperglycaemia, and the abdominal VAT played a better predictive role for the risk of MetS.

Low-dose spironolactone combats dyslipidemia and hepatic inflammation by modulating PCSK9 in rat model of polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder among women and it is associated with overt metabolic derangement. Circulating lipids are regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9) which blocks low density lipoprotein (LDL) receptors especially in the liver. The liver is highly vulnerable in dyslipidemia as lipid accumulation leads to progression of non-alcoholic fatty liver disease (NAFLD). An array of scientific endeavours hold that low-dose spironolactone (LDS) is beneficial as intervention for PCOS traits, but this claim is yet to be fully elucidated. The aim of this study was to investigate the effect of LDS on dyslipidemia and hepatic inflammation in rats with letrozole (LET)-induced PCOS and to assess the possible involvement of PCSK9 in these effects. Eighteen female Wistar rats were randomly assigned into 3 groups. The control group received vehicle (distilled water; p.o.), LET-treated group received letrozole (1 mg/kg; p.o.), LET+LDS-treated group received LET plus LDS (0.25 mg/kg, p.o.) for 21 days. Exposure to LET increased body and hepatic weights, plasma and hepatic total cholesterol (TC), TC/HDL, LDL, interleukin-6, MDA, PCSK9, ovarian degenerated follicles and hepatic NLRP3 intensity, reduced GSH and normal ovarian follicles. Interestingly, LDS averted dyslipidemia, NLRP3-dependent hepatic inflammation and ovarian PCOS traits. It is evident herein that LDS ameliorates PCOS traits and combats dyslipidemia and hepatic inflammation in PCOS by a PCSK9-dependent mechanism.

New perspectives in diabetic neuropathy.

Diabetes prevalence continues to climb with the aging population. Type 2 diabetes (T2D), which constitutes most cases, is metabolically acquired. Diabetic peripheral neuropathy (DPN), the most common microvascular complication, is length-dependent damage to peripheral nerves. DPN pathogenesis is complex, but, at its core, it can be viewed as a state of impaired metabolism and bioenergetics failure operating against the backdrop of long peripheral nerve axons supported by glia. This unique peripheral nerve anatomy and the injury consequent to T2D underpins the distal-to-proximal symptomatology of DPN. Earlier work focused on the impact of hyperglycemia on nerve damage and bioenergetics failure, but recent evidence additionally implicates contributions from obesity and dyslipidemia. This review will cover peripheral nerve anatomy, bioenergetics, and glia-axon interactions, building the framework for understanding how hyperglycemia and dyslipidemia induce bioenergetics failure in DPN. DPN and painful DPN still lack disease-modifying therapies, and research on novel mechanism-based approaches is also covered.

Reshaping the gut microbiome and bile acid composition by Gyejibongnyeong-hwan ameliorates western diet-induced dyslipidemia.

Gyejibongnyeong-hwan (GBH), a traditional Chinese medicine, is used in clinical practice to treat blood stasis in metabolic diseases. Herein, we examined the effects of GBH on dyslipidemia and investigated the underlying mechanisms by focusing on modulation of the gut microbiota-bile acid axis by GBH. We utilized a Western diet-induced dyslipidemia mouse model and divided animals into the following four groups (n = 5 each): the normal chow diet, vehicle control (WD), simvastatin (Sim, 10 mg/kg/day simvastatin; positive control), and GBH (GBH, 300 mg/kg/day) groups. The drugs were administered for 10 weeks, and morphological changes in the liver and aorta were analyzed. The mRNA expression of genes related to cholesterol metabolism, gut microbiota, and bile acid profiles were also evaluated. The GBH group showed significantly lower levels of total cholesterol, accumulation of lipids, and inflammatory markers in the liver and aorta of Western diet-fed mice. Low-density lipoprotein cholesterol levels were significantly lower in the GBH group than in the WD group (P < 0.001). The expression of cholesterol excretion-associated genes such as liver X receptor alpha and ATP-binding cassette subfamily G member 8, as well as the bile acid synthesis gene cholesterol 7 alpha-hydroxylase, which lowers cholesterol in circulation, was increased. Furthermore, GBH inhibited the intestinal farnesoid X receptor (FXR)-fibroblast growth factor 15 signaling pathway through the interactions of gut microbiota with bile acids acting as FXR ligands, which included chenodeoxycholic acid and lithocholic acid. Overall, GBH improved dyslipidemia induced by a Western diet by modulating the gut microbiota-bile acid axis.

Role of PPARγ in dyslipidemia and altered pulmonary functioning in mice following ozone exposure.

Exposure to ozone causes decrements in pulmonary function, a response associated with alterations in lung lipids. Pulmonary lipid homeostasis is dependent on the activity of peroxisome proliferator activated receptor gamma (PPARγ), a nuclear receptor that regulates lipid uptake and catabolism by alveolar macrophages (AMs). Herein, we assessed the role of PPARγ in ozone-induced dyslipidemia and aberrant lung function in mice. Exposure of mice to ozone (0.8 ppm, 3 h) resulted in a significant reduction in lung hysteresivity at 72 h post exposure; this correlated with increases in levels of total phospholipids, specifically cholesteryl esters, ceramides, phosphatidylcholines, phosphorylethanolamines, sphingomyelins, and di- and triacylglycerols in lung lining fluid. This was accompanied by a reduction in relative surfactant protein-B (SP-B) content, consistent with surfactant dysfunction. Administration of the PPARγ agonist, rosiglitazone (5 mg/kg/day, i.p.) reduced total lung lipids, increased relative amounts of SP-B, and normalized pulmonary function in ozone-exposed mice. This was associated with increases in lung macrophage expression of CD36, a scavenger receptor important in lipid uptake and a transcriptional target of PPARγ. These findings highlight the role of alveolar lipids as regulators of surfactant activity and pulmonary function following ozone exposure and suggest that targeting lipid uptake by lung macrophages may be an efficacious approach for treating altered respiratory mechanics.

Prevention of High-Fat-Diet-Induced Dyslipidemia by Lactobacillus plantarum LP104 through Mediating Bile Acid Enterohepatic Axis Circulation and Intestinal Flora.

This work aimed to investigate the alleviative mechanism of Lactobacillus plantarum LP104 (LP104) isolated from kimchi on high-fat-diet-induced dyslipidemia by targeting the intestinal flora and bile acid (BA) metabolism. Oral administration of LP104 over 8 weeks reduced body weight gain and body fat, as well as ameliorating serum and hepatic dyslipidemia in HFD-fed C57BL/6N mice significantly. LP104 intervention also increased the ileal tauro-α/ß-muricholic acid sodium salt (T-α-MCA or T-ß-MCA) and tauroursodeoxycholic acid (TUDCA) concentrations to suppress the enterohepatic farnesoid X receptor/fibroblast growth factor 15-fibroblast growth factor receptor 4 (FXR/FGF15-FGFR4) signaling pathway, which stimulated the hepatic cholic acid (CA) and chenodeoxycholic acid (CDCA) de novo synthesis through using cholesterol. Then, LP104 treatment accelerated BA excretion with the feces and cholesterol efflux to improve HFD-caused hyperlipidemia effectively. The 16S rRNA gene high-throughput sequencing revealed that LP104 promoted intestinal flora rebalance by increasing the abundances of Bacteroides, Akkermansia, Lactobacillus, and Clostridium and decreasing the abundance of Oscillospira and Coprococcus. Meanwhile, Spearman correlation analysis demonstrated that the differential flora were closely related to BA signaling molecules including CA, CDCA, T-α-MCA, T-ß-MCA, and TUDCA after LP104 intervention. These findings provided new evidence that LP104 had the potential to be used as a naturally functional food for the prevention of dyslipidemia.