Decreased Serum Low-density Lipoprotein Cholesterol Research Articles

Dietary L-theanine supplementation improves antioxidant capacity and lipid metabolism in finishing pigs

The objective of this study was to investigate the effects of dietary L-theanine (LTH) supplementation on finishing pigs' antioxidant capacity and lipid metabolism. Results showed that dietary LTH supplementation increased the activity of antioxidant enzymes and decreased the content of malondialdehyde in serum, longissimus dorsi muscle (LD muscle), and liver of finishing pigs (P < 0.05). Dietary LTH supplementation decreased serum low-density lipoprotein cholesterol content and increased high-density lipoprotein cholesterol content (P < 0.05). Moreover, LTH-containing diet decreased the contents of triglyceride and total cholesterol in serum, LD muscle, and liver (P < 0.05). In liver and LD muscle, LTH activated Nrf2-Keap1 signaling pathway, increased mRNA expression levels of genes related to lipolysis and fatty acid oxidation and reduced the expression levels of genes related to adipogenesis (P < 0.05). According to our study, nutritional supplementation with LTH enhanced finishing pigs' antioxidant capacity and lipid metabolism.

ARO-ANG3, an investigational RNAI therapeutic, decreases serum LDL-cholesterol, apolipoprotein B, and angiopoietin-like protein 3 in patients with homozygous familial hypercholesterolaemia

ARO-ANG3, an investigational RNAI therapeutic, decreases serum LDL-cholesterol, apolipoprotein B, and angiopoietin-like protein 3 in patients with homozygous familial hypercholesterolaemia

Rosuvastatin treatment alone cannot alleviate lupus in murine model: a pilot study.

Systemic lupus erythematosus (SLE) is an autoimmune disease, characterized by the production of autoantibodies and high cholesterol levels. HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors have exhibited anti-inflammatory effects in several clinical trials. We conducted this study to evaluate the effect of rosuvastatin on inflammatory responses in lupus-prone mice. MRL/lpr mice were intraperitoneally injected with rosuvastatin (10 mg/kg, n=4) or vehicle (2% dimethyl sulfoxide, n=4) five times a week from 13 to 17 weeks of age. The serum levels of low-density lipoprotein (LDL) cholesterol and autoantibodies were measured, as well as the urine levels of albumin. Renal tissues were stained for histopathological analysis. Concentrations of key inflammatory cytokines were measured in the serum, and messenger RNA (mRNA) levels in target organs (kidney, spleen, and lymph nodes) were evaluated. Rosuvastatin treatment significantly decreased serum LDL cholesterol concentration in MRL/lpr mice. However, the clinical manifestations and autoantibody titres did not improve with rosuvastatin treatment. In addition, serum inflammatory cytokines and proteinuria did not change. Histopathological analysis of the kidneys revealed no improvement. When assessing the expression of mRNA, treatment with rosuvastatin decreased tumor necrosis alpha and interleukin-17 concentration in spleen and kidney tissue and in the kidneys and lymph nodes of MRL/lpr mice, respectively. Although it can decrease inflammatory cytokines in the lymphoid organs and kidneys of MRL/lpr mice, treatment with rosuvastatin is insufficient to alleviate SLE.

Dietary Forsythia suspensa extracts supplementation improves antioxidant status, anti-inflammatory functions, meat fatty acid deposition, and intestinal microbial community in finishing pigs.

This study aimed to determine the effects of Forsythia suspensa extracts (FSE) on performance, antioxidant status, inflammatory cytokines, meat quality, meat fatty acid composition, and gut microbial community in finishing pigs. Sixty-four pigs [Duroc × (Landrace × Yorkshire)] with an average initial body weight of 88.68 kg were randomly allotted to two dietary treatments, with eight replicate pens per treatment (four pens were barrows and four pens were gilts), four pigs per pen. The dietary treatments included a corn–soybean meal basal diet (CON) and an FS diet (basal diet + 100 mg/kg FSE; FS). Compared with CON, pigs fed FSE showed enhanced (P < 0.05) saturated fatty acid (SFA)/polyunsaturated fatty acid (PUFA) ratio, reduced (P < 0.05) lightness, and n−6/n−3 PUFA ratio, as well as tended to increase C20:5n3 content in the longissimus dorsi muscle. Moreover, pigs fed FSE showed decreased (P < 0.05) serum cortisol and tumor nuclear factor-α contents, and increased (P < 0.05) serum high-density lipoprotein cholesterol, superoxide dismutase, and glutathione peroxidase contents compared with CON. These pigs also tended to have increased serum total protein and immunoglobulin G contents, and decreased serum low-density lipoprotein cholesterol and interleukin-1β contents compared with CON. In the colon, pigs fed FSE had a higher (P < 0.05) relative abundance of Bifidobacteriales at the order level, Lactobacillaceae and Bifidobacteriaceae at the family level, as well as Lactobacillus and Bifidobacterium at the genus level compared with CON. In conclusion, dietary Forsythia suspensa extract supplementation effectively improved antioxidant status and anti-inflammatory functions, as well as modulated meat fatty acid composition, and gut microbial community in finishing pigs.

Curcumin nicotinate decreases serum LDL cholesterol through LDL receptor-mediated mechanism

Curcumin nicotinate (Curtn) is a synthesized ester derivative of curcumin and niacin. Our previous study has shown that Curtn lowers serum low-density lipoprotein cholesterol (LDL-C) levels in apoE−/− mice and promotes LDL-C uptake into HepG2 cells in vitro. The present study was to test the hypothesis that Curtn decreases serum LDL-C levels through decreased expression of pro-protein convertase subtilisin/kexin type 9 (PCSK9) and subsequent increase in LDL receptor expression. Male Wistar rats on high-fat diet (HFD) were treated with Curtn or rosuvastatin. Curtn or rosuvastatin treatment significantly decreased serum levels of total cholesterol (TC) and LDL-C in rats on HFD with increased liver LDL receptor expression. LDL-C-lowering effect of Curtn was not observed in LDL receptor deficient (LDLR−/−) mice on HFD, while rosuvastatin still decreased serum lipid levels in LDLR−/− mice, indicating that the reduction of serum LDL-C levels by Curtn treatment was LDL receptor-dependent. Curtn treatment also significantly decreased the protein expression of PCSK9 in Wistar rats and LDLR−/− mice. In HepG2 cells with overexpression of human PCSK9, Curtn treatment significantly increased LDL-C uptakes into hepatocytes, and increased LDL receptor distribution on cell surface in association with decreased PCSK9 protein expression. RNAi-LDLR significantly attenuated the effect of Curtn on LDLR distribution on cell surface. These data indicates that Curtn would decrease serum LDL-C level at least partially through inhibition of PCSK9 expression, and subsequent increase in LDL receptor expression and distribution in hepatocytes, serving as a potential novel compound to treat hyperlipidemia.

Beneficial effects of silkworm (Bombyx mori) pupal oil on serum and hepatic lipid parameters in high fat diet fed rats

As a kind of insect oil, silkworm (Bombyx mori) pupal oil (SPO) is rich in abundant nutritive components including unsaturated fatty acids especially alpha-linolenic acid, and can bring significant economic benefits. SPO extracted by supercritical carbon dioxide from desilked silkworm pupae was employed to investigate the beneficial effects of SPO on growth parameters and lipid metabolism of rats fed with high-fat diet (HFD). Results demonstrated that SPO supplementation could reduce the body weight gain and relative liver weight and it could lower the total cholesterol and triglycerides in serum and liver in HFD fed rats. It significantly decreased serum low-density lipoprotein-cholesterol (LDL-C) levels and increased serum and hepatic high-density lipoprotein-cholesterol (HDL-C) level in HFD rats. Hepatic protection by SPO was confirmed by histological analysis of the liver via H&amp;E staining. SPO relieved the negative effect of HFD on the mRNA expression of lipoprotein lipase (LPL), toll-like receptor 4, and nuclear factor-kappa B p65 in the liver. Our study indicates that SPO is a promising dietary supplement regulating lipid metabolism and potentially contributes to the prevention and therapy of fatty liver diseases such as obesity-related atherosclerosis.

Effects of time-restricted feeding and type of food on fertility competence in female mice

We assessed the effects of feeding regimen (ad libitum vs. time-restricted food access) and type of food (normal chow (NC: 12% fat) vs. moderately high calorie diet (mHCD: 31% fat)) on fertility competence of female mice. Mice fed mHCD had higher number of oocytes than mice fed NC. On the other hand, when mice were fed NC under time-restricted access to food (NT), the developmental rate to the blastocyst per number of normally fertilized ova was significantly decreased compared to others. The reactive oxygen species (ROS) level in oocytes increased in time-restricted food access and NC group. Transcriptome analysis of whole ovarian tissues from these mice showed a change in the cholesterol metabolism among the four groups. Time-restricted food access decreased serum LDL cholesterol level in both NC and mHCD groups. Moreover, the number of atretic follicles increased in NT mice compared to ad libitum food access mice. The present study shows that mHCD feeding increases the number of ovulated oocytes and that time-restricted feeding of NC impairs the developmental competence of oocytes after fertilization, probably due to the changes in serum cholesterol levels and an increase in the ROS content in oocytes.

Canned Beans Decrease Serum Total and LDL Cholesterol in Adults with Elevated LDL Cholesterol in a 4-wk Multicenter, Randomized, Crossover Study

BackgroundPractical risk reduction strategies are needed to address cardiovascular disease. Beans can decrease LDL cholesterol; however, research into different daily amounts and varieties is warranted. ObjectivesTo examine the effects of canned beans (daily rotation of black, navy, pinto, dark red kidney, white kidney) in 1-cup (1CB, 180 g) and ½-cup (½CB, 90 g) daily amounts compared with a 1-cup white rice (WR) control on serum lipid and glycemic biomarkers in adults with elevated LDL cholesterol. MethodsAdults [n = 73, mean ± SD age: 48.1 ± 14.2 y; BMI (in kg/m2): 25.9 ± 4.22; fasting serum LDL cholesterol: 3.0–5.0 mmol/L] consumed 1CB, ½CB, and WR for 4-wk treatment periods separated by ≥4-wk washouts in a multicenter, randomized, crossover study. Fasting serum LDL cholesterol (primary outcome) and other lipids and glycemic biomarkers (secondary outcomes) were measured on study days 1 and 29 of each treatment period with study day 29 values compared using repeated-measures ANCOVA, including study day 1 values as covariates. ResultsTreatment completion was n = 66 for 1CB, n = 68 for ½CB, and n = 64 for WR. Total cholesterol on study day 29 was lower for 1CB (P = 0.04) but not ½CB (P = 0.77) compared with WR (–5.46%, –2.74%, –0.65% changes from study day 1, respectively) and did not differ between 1CB and ½CB (P = 0.17). LDL cholesterol on study day 29 was also lower for 1CB (P = 0.002) but not ½CB (P = 0.30) compared with WR (–8.08%, –3.84%, +0.49% changes from study day 1, respectively) and did not differ between 1CB and ½CB (P = 0.11). Other lipids and glycemic biomarkers did not differ among treatments. ConclusionsConsumption of 1 cup (180 g) of canned beans of multiple varieties decreased total and LDL cholesterol in adults with elevated LDL cholesterol, supporting a practical strategy for cardiovascular disease risk reduction. This trial was registered at http://clinicaltrials.gov as NCT03830970.

Effects of sitagliptin on serum lipid levels in patients with type 2 diabetes: a systematic review and meta-analysis.

Lipid abnormalities often occur in patients with diabetes mellitus and the coexistence of diabetes mellitus and dyslipidaemia will increase the risk of cardiovascular diseases. However, the specific effects of sitagliptin on lipid control remain elusive in diabetic patients. The aim of this meta-analysis is to investigate the effects of sitagliptin alone or with other antidiabetic agents on serum lipid control. PubMed, Cochrane Library, Embase and the ClinicalTrials.gov website were systematically searched from 2006 (the first year that sitagliptin entered market) to 16 January 2021. Eligible studies were randomized clinical trials (RCTs) of sitagliptin including outcomes of serum total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C) or low-density lipoprotein cholesterol (LDL-C). A total of 14 RCTs with 2654 patients were identified. Treatment with sitagliptin alone or in combination with other antidiabetic agents significantly reduced serum TC [mean difference (MD) = -5.52 95% confidence interval (95% CI), -7.88 to -3.15; P < 0.00001] and LDL-C (MD = -0.07; 95% CI, -0.14 to 0.00; P < 0.00001) in patients with type 2 diabetes. No statistical significances were found in serum triglycerides (MD = 1.53; 95% CI, -8.22 to 11.28; P = 0.76) or HDL-C (MD = 0.65; 95% CI, -1.59 to 0.29; P = 0.18). Subgroup analyses suggest that sitagliptin can significantly decrease serum LDL-C, TC and triglyceride levels compared with placebo alone, and no statistical significance was found in comparison with the serum HDLC levels. Sitagliptin alone or in combination with other antidiabetic agents significantly reduces serum TC and LDL-C in patients with type 2 diabetes mellitus, while no significant difference was observed in serum triglycerides or HDL-C.

Serum trimethylamine-N-oxide and gut microbiome alterations are associated with cholesterol deposition in the liver of laying hens fed with rapeseed meal.

Sinapine derived from cruciferous plants could be converted into trimethylamine by intestinal microbiota. Its metabolite, trimethylamine N-oxide (TMAO), is closely linked to increased risk of cardiovascular disease and fat deposition in mammals. Hens fed with rapeseed meal (RSM) suffered from fatty liver hemorrhage syndrome (FLHS). This study was conducted to investigate whether RSM-induced fatty liver is due to TMAO via altering microbiota composition and diversity. At 33 weeks of age, 600 laying hens were randomly divided into 5 treatment groups, namely control and 14% RSM treatment groups (DY5, with 16.2% erucic acid [EA] and 74.66% glucosinolate [Gl] contents; MB1, with 3.50% EA and 43.23% Gl contents; DY6, with 6.7% EA and 22.67% Gl contents; XH3, with 44.60% EA and 132.83% Gl contents) for 8 weeks. Results revealed that 3 hens died due to liver hemorrhage after ingesting 14% RSM diet. The 14% RSM decreased serum low-density lipoprotein cholesterol (LDL-C) content (P < 0.01) while tended to increase serum TMAO content compared to the control group (P = 0.08). The 14% RSM diet increased red oil O optical density (P < 0.01), and increased total cholesterol (TC) and LDL-C content in the liver (P < 0.01, and P < 0.01, respectively). The 14% RSM decreased liver total bile acid (TBA) content compared to the control (P < 0.01). The DY6 had a higher TBA content in the liver than the XH3 (P < 0.01). The 14% RSM decreased mRNA abundance of liver X receptors alpha (LXR-α, P = 0.01), and increased mRNA abundance of sterol response element binding protein 2 (SREBP-2, P = 0.04). Results revealed that the in-feed RSM could alter richness and diversity of cecal microbiota compared to the control (P < 0.05). Liver TC content and serum TMAO showed a negative relationship with Proteobacteria and Actinobacteria (P = 0.04). In conclusion, 14% RSM increased liver TC and induced high liver score of FLHS, which was possibly associated with the altered cecal microbiota composition, increased serum TMAO levels and LXR-α and SREBP-2 expressions.

New Insight Into Metformin-Induced Cholesterol-Lowering Effect Crosstalk Between Glucose and Cholesterol Homeostasis via ChREBP (Carbohydrate-Responsive Element-Binding Protein)-Mediated PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Regulation.

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Plant Stanol Esters Reduce LDL (Low-Density Lipoprotein) Aggregation by Altering LDL Surface Lipids: The BLOOD FLOW Randomized Intervention Study.

Plant stanol ester supplementation (2-3 g plant stanols/d) reduces plasma LDL (low-density lipoprotein) cholesterol concentration by 9% to 12% and is, therefore, recommended as part of prevention and treatment of atherosclerotic cardiovascular disease. In addition to plasma LDL-cholesterol concentration, also qualitative properties of LDL particles can influence atherogenesis. However, the effect of plant stanol ester consumption on the proatherogenic properties of LDL has not been studied. Approach and Results: Study subjects (n=90) were randomized to consume either a plant stanol ester-enriched spread (3.0 g plant stanols/d) or the same spread without added plant stanol esters for 6 months. Blood samples were taken at baseline and after the intervention. The aggregation susceptibility of LDL particles was analyzed by inducing aggregation of isolated LDL and following aggregate formation. LDL lipidome was determined by mass spectrometry. Binding of serum lipoproteins to proteoglycans was measured using a microtiter well-based assay. LDL aggregation susceptibility was decreased in the plant stanol ester group, and the median aggregate size after incubation for 2 hours decreased from 1490 to 620 nm, P=0.001. Plant stanol ester-induced decrease in LDL aggregation was more extensive in participants having body mass index<25 kg/m2. Decreased LDL aggregation susceptibility was associated with decreased proportion of LDL-sphingomyelins and increased proportion of LDL-triacylglycerols. LDL binding to proteoglycans was decreased in the plant stanol ester group, the decrease depending on decreased serum LDL-cholesterol concentration. Consumption of plant stanol esters decreases the aggregation susceptibility of LDL particles by modifying LDL lipidome. The resulting improvement of LDL quality may be beneficial for cardiovascular health. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01315964.

Effects of Mixed Nut Consumption on LDL Cholesterol and Lipoprotein(a) in Overweight and Obese Adults

Abstract Objectives Elevated levels of LDL cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] are associated with a greater risk for atherosclerotic cardiovascular events. Consumption of individual types of nuts has been shown to decrease these risk factors but limited knowledge is known about the effect of mixed nuts on Lp(a). Very few studies have evaluated the effect of mixed nut consumption on LDL-C levels in an obese and overweight population, while even fewer studies have examined the effects of a dietary intervention on Lp(a). The objective of this study was to determine if 69 g/d of mixed nut consumption would decrease serum LDL-C and Lp(a) levels in obese and overweight individuals. Methods In a randomized-controlled 16-week study, 29 obese or overweight (BMI 25–40 kg/m2, age 27.6 years) participants were asked to consume either 69 g of mixed nuts/d (n = 15) or 42.5 g of isocaloric-matched Snyder's unsalted pretzels/d (n = 14). Blood samples were collected at baseline, week 8, and week 16 for analysis of total cholesterol (TC), LDL-C, HDL-C, oxidized-LDL (OxLDL), triglyceride (TG) and Lp(a). Results There were no significant differences in TC, LDL-C, HDL-C, OxLDL, or Lp(a) when comparing the two intervention diets. Participants consuming mixed nuts had significantly higher (P = 0.007) serum TGs when compared to the pretzel group at week 8 but differences were not significant at week 16. Conclusions Consumption of mixed nuts (69 g/d) had no effect on LDL-C or Lp(a) levels over a 16-week dietary intervention in an obese or overweight population. Future direction should focus on increasing sample size and/or testing for confounding traits (i.e., polymorphisms, metabolic syndrome, or predispositions to elevated LDL-C levels). Funding Sources American Heart Association (16GRNT31360007).

Protective effects of alendronate in Triton X-100-induced hyperlipidemia in rats.

The aim of the present study was to evaluate the protective effects of alendronate (used in osteoporosis disease) in Triton X-100 (a polyethylene glycol-based non-ionic surfactant)-induced hyperlipidemia in rats. The animals were randomized into seven groups receiving different treatments for 21 days, and alendronate was administered (1.5 and 3 mg/kg body weight, per orally (p.o.) by oral gavage). On day 21, the rats were anesthetized and decapitated, blood samples were extracted, and the livers were dissected for various biochemical tests and histopathological examinations. The biochemical parameters, total cholesterol (TC), triglycerides (TGs), low-density lipoprotein-cholesterol (LDL-C), very low-density lipoprotein-cholesterol (VLDL-C), thiobarbituric acid reactive substances (TBARS), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and atherogenic index, were increased, and reduction in high-density lipoprotein-cholesterol (HDL-C) levels was observed following Triton X-100 treatment to rats. Alendronate (1.5 and 3 mg/kg) produced a dose-dependent reduction in serum TC, VLDL-C, TGs, ratio of TC/HDL-C, ALT, AST, and TBARS. It significantly increased the HDL-C and superoxide dismutase levels but did not cause a significant decrease in serum LDL-C and/or an increase in catalase levels. Histopathological examinations of alendronate showed beneficial effects with lower capsular thickening, slight enlargement of the hepatocytes at the margin, and lower inflammatory cell infiltration. Alendronate showed dose-dependent antihyperlipidemic and hepatoprotective effects. It may serve a dual purpose as anti-osteoporotic and hypolipidemic by reducing blood cholesterol and TG synthesis and offering hepatic protection.

Pharmacological Strategies beyond Statins: Ezetimibe and PCSK9 Inhibitors.

Dyslipidemia, highly elevated, low-density lipoprotein (LDL) cholesterol, is a major cardiovascular risk factor. Statins have been proven to effectively reduce the risk of atherosclerotic cardiovascular disease (ASCVD) and are recommended as a first-line therapy for the primary and secondary prevention of ASCVD. However, statins may not be sufficient in decreasing LDL cholesterol levels and pose a significant on-treatment residual risk of major cardiovascular events (i.e., residual cholesterol risk) according to meta-analyses of statin trials. Current guidelines for cholesterol management to achieve additional LDL cholesterol reduction and reduce ASCVD risk recommend two hyperlipidemic agents besides statins. Use of ezetimibe, a cholesterol absorption inhibitor, leads to additional LCL cholesterol reduction and decreased ASCVD risk, when added to statin therapy, without raising significant safety concerns. Furthermore, in combination with a mild-to-moderate statin intensity, ezetimibe is used in situations of statin-associated adverse effects such as myalgia and the combination therapy is relatively safer. Monoclonal antibody of proprotein convertase subtilisin/kexin type 9 (PCSK9), alirocumab, and evolocumab, have been approved to lower LDL cholesterol level. While there are drawbacks to the use of PCSK9 inhibitors, including high cost and adverse events such as injection site reaction, they significantly decreased serum LDL cholesterol levels and thereby ASCVD risks when added to maximally tolerated statin therapy.

Hyperlipidemia: Management with Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors.

Coronary artery disease is the leading cause of death in United States. Hyperlipidemia is an independent and potentially reversible risk factor for coronary artery disease. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, collectively known as statins, have been the mainstay of pharmacologic therapy. Their availability, ease of administration, low cost, and strong evidence behind safety and efficacy makes them one of the most widely prescribed lipid-lowering agents. However, some patients may be intolerant to statins, and few others suffer from very high serum levels of cholesterol in which statin therapy alone or in combination with other cholesterol-lowering agents is insufficient in reducing serum lipid levels to achieve desired levels. In 2015, the Food and Drug Administration approved a new family of lipid-lowering agents, collectively known as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.PCSK9 inhibitors are biologically active molecules that decrease serum low-density lipoprotein cholesterol compared with statin therapy alone. They serve as an alternative to statins for patients who are intolerant to statin or as supplemental therapy in those patients for whom lower levels in serum low-density lipoprotein cholesterol are not achieved by statins alone. This article discusses PCSK9 inhibitors, their mechanism of action, indications, efficacy, safety, costs and limitations.

The Different Effects of Sodium Glucose Cotransporter 2 Inhibitor on Obese Diabetic Mice Fed a Normal or Low-Carbohydrate Diet

Sodium glucose co-transporter 2 inhibitors (SGLT2i) are antidiabetic drugs for type 2 diabetes that lower blood glucose levels and induce weight loss. However, the efficacy of SGLT2i is known to be affected by dietary factors such as carbohydrate and fat intake. In this study, we compared the effects of the SGLT2i (dapagliflozin) in eight-week-old male KK-Ay mice (a diabetic obese model) pair-fed a normal carbohydrate diet (NCD; carbohydrate 65, protein 23, fat 12%) or a low carbohydrate diet (LCD; carbohydrate 20, protein 45, fat 35%) for 8 weeks with or without dapagliflozin (5 mg/kg p.o.) (n=5-6). Dapagliflozin reduced body weight gain and blood glucose levels in the fed state in NCD and LCD, but reduced fasting blood glucose levels in NCD only. Likewise, dapagliflozin ameliorated glucose intolerance and enhanced hepatic gluconeogenesis in NCD only. Dapagliflozin decreased serum LDL cholesterol levels and subcutaneous fat in both groups, but decreased epidydimal fat (a visceral fat) in NCD only. We then investigated the metabolic effects of dapagliflozin and their underlying mechanisms in liver using transcriptomics (DNA microarray analysis) and metabolomics (Capillary Electrophoresis-Mass Spectrometry: CE-MS and Liquid Chromatography-Mass spectrometry: LC/MS). Dapagliflozin upregulated the expression of genes related to gluconeogenesis and β-oxidation in liver in both groups. In NCD, dapagliflozin increased several kinds of amino acids, and in LCD, it increased ketone bodies. Dapagliflozin upregulated the expression of genes related to bile acid metabolism in NCD only. Both groups showed a reduction in cholesterol ester, a major component of LDL cholesterol, in liver. Our results suggest that the efficacy of SGLT2i is attenuated under LCD, and that differences in liver metabolism between NCD and LCD under dapagliflozin treatment contribute to this outcome. Disclosure F. Furuya: None. Y. Fujita: Research Support; Self; AstraZeneca, Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, MSD K.K., Eli Lilly and Company. N. Matsuo: None. Y. Oguri: None. H. Minamino: None. K. Ikeda: None. S. Harashima: Advisory Panel; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; Sanofi K.K.. Research Support; Self; Sanofi K.K.. Speaker's Bureau; Self; Tanabe Mitsubishi KK. Advisory Panel; Self; Tanabe Mitsubishi KK. Speaker's Bureau; Self; Novartis Pharma K.K., Eli Lilly and Company, Ono Pharmaceutical Co., Ltd.. Y. Wang: None. Y. Liu: None. N. Inagaki: Research Support; Self; Daiichi Sankyo Company, Limited, AstraZeneca, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited, Japan Tobacco Inc., MSD K.K., Sumitomo Dainippon Pharma Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Kissei Pharmaceutical Co., Ltd., Novo Nordisk Pharma Ltd., Eli Lilly and Company, Sanwa Chemical Industrial Co., Ltd., Teijin Pharma Limited.

Novel approaches to lipid-lowering therapy

Cardiovascular disease (CVD) remains a major cause of death worldwide, with dyslipidaemia playing a significant role in the disease process. It is clinically useful to demarcate hypercholesterolaemia from hypertriglyceridaemia, with an increased serum low-density lipoprotein (LDL) cholesterol being the most powerful predictor of CVD morbidity and mortality, and a significant elevation in triglyceride levels increasing the risk of acute pancreatitis. Statins (with or without ezetimibe) and fibrates are the current first-line therapy in the management of dyslipidaemia. Although these medications have shown effectiveness in reducing CVD complications, there are patients who require a greater modification in lipid profile or are intolerant of first-line therapy. Novel agents are on the horizon, which have shown to lead to a significant decrease in serum LDL cholesterol. These include the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (which have shown a reduction in CVD morbidity), mipomersen, cholesterol ester transfer protein (CETP) inhibitors and bempedoic acid. Further studies of the clinical benefit of these medications are ongoing. Drugs such as pemfibrate, angiopoietin-like protein 3 (ANGPTL3) inhibitors, apolipoprotein C3 (apo C3) inhibitors and diacylglycerol acyltransferase-1 (DGAT 1) inhibitors have shown promising results in the management of hypertriglyceridaemia. It is hoped that these exciting new technological advancements in the future management of dyslipidaemia will result in clinical benefit for patients.

PCSK9 Inhibitors: Mechanism of Action, Efficacy, and Safety.

Low-density lipoprotein (LDL) receptors on the surface of liver hepatocytes are the primary way that humans regulate serum LDL cholesterol levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a proteolytic enzyme that indirectly regulates serum LDL cholesterol (LDL-C) by causing the destruction of LDL receptors. Less LDL receptors result in increased LDL-C in the bloodstream but inhibiting or binding the circulating PCSK9 results in increased LDL receptors with the resultant decrease in serum LDL-C. Two PCSK9 inhibitors are currently approved for use: alirocumab and evolocumab. Both are fully human monoclonal antibodies that bind free PCSK9. Herein we discuss the mechanism of action, efficacy, and safety of PCSK9 inhibitors. clinical problem.

Targeting Sirt1 in a rat model of high-fat diet-induced non-alcoholic fatty liver disease: Comparison of Gegen Qinlian decoction and resveratrol.

The present study aimed to explore the mechanism of action of Gegen Qinlian decoction (GGQLD) in experimental non-alcoholic fatty liver disease (NAFLD). A total of 30 rats were randomly divided into five groups: The chow, model, high- and low-dose GGQLD (GGQLD-H and GGQLD-L, respectively) and resveratrol (Resl) groups, and were treated with saline, GGQLD and Resl when a model of high-fat diet (HFD)-induced NAFLD was established. Blood lipid and liver enzymes were detected following treatment for 8 weeks and liver tissue pathology was observed using Oil Red O and haematoxylin and eosin staining. Furthermore, the liver protein and mRNA expression of sirtuin (Sirt)1, peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) were measured using western blotting and reverse transcription-quantitative polymerase chain reaction. Compared with the chow group, the model group demonstrated significantly increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (P<0.01). GGQLD doses and Resl attenuated the elevated serum ALT and AST levels. GGQLD-H and Resl significantly increased the serum high-density lipoprotein cholesterol level compared with that in the model group (P<0.01), while GGQLD-L and Resl significantly decreased serum low-density lipoprotein cholesterol levels (P<0.01). The GGQLDs and Resl groups revealed an evident improvement in Sirt1 protein and mRNA expression. Although GGQLD and Resl significantly decreased NF-κB gene expression compared with the model group (P<0.01), the effect on NF-κB protein expression was not significant. Furthermore, the PGC-1α gene and protein expression in the HFD rat group slightly decreased compared to the levels in the chow group, but the decrease was insignificant. However, an evident increase in PGC-1α mRNA expression was observed in the GGQLD-H group compared with the model group (P<0.01). Histological staining revealed that GGQLD and Resl decreased the lipid droplets in hepatocytes and normalized steatosis in rats fed with a HFD. The results indicated that GGQLD treatment may be a potent strategy for managing NAFLD by managing lipid metabolism and inflammatory and histological abnormalities by triggering the Sirt1 pathway.