A structurally optimized FXR agonist, MET409, reduced liver fat content over 12 weeks in patients with non-alcoholic steatohepatitis.

BACKGROUND & AIMS: The benefits of farnesoid X receptor (FXR) agonists in patients with non-alcoholic steatohepatitis (NASH) have been validated, although improvements in efficacy and/or tolerability remain elusive. Herein, we aimed to assess the performance of a structurally optimized FXR agonist in patients with NASH. METHODS: In this 12-week, randomized, placebo-controlled study, we evaluated MET409 - a non-bile acid agonist with a unique chemical scaffold - in patients with NASH. Patients were randomized to receive either 80 mg (n = 20) or 50 mg (n = 19) of MET409, or placebo (n = 19). RESULTS: At Week 12, MET409 lowered liver fat content (LFC), with mean relative reductions of 55% (80 mg) and 38% (50 mg) vs. 6% in placebo (p <0.001). MET409 achieved ≥30% relative LFC reduction in 93% (80 mg) and 75% (50 mg) of patients vs. 11% in placebo (p <0.001) and normalized LFC (≤5%) in 29% (80 mg) and 31% (50 mg) of patients vs. 0% in placebo (p <0.05). An increase in alanine aminotransferase (ALT) was observed with MET409, confounding Week 12 changes from baseline (-25% for 80 mg, 28% for 50 mg). Nonetheless, MET409 achieved ≥30% relative ALT reduction in 50% (80 mg) and 31% (50 mg) of patients vs. 17% in placebo. MET409 was associated with on-target high-density lipoprotein cholesterol decreases (mean changes of -23.4% for 80 mg and -20.3% for 50 mg vs. 2.6% in placebo) and low-density lipoprotein cholesterol (LDL-C) increases (mean changes of 23.7% for 80 mg and 6.8% for 50 mg vs. -1.5% in placebo). Pruritus (mild-moderate) occurred in 16% (50 mg) and 40% (80 mg) of MET409-treated patients. CONCLUSION: MET409 lowered LFC over 12 weeks in patients with NASH and delivered a differentiated pruritus and LDL-C profile at 50 mg, providing the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced through structural optimization. LAY SUMMARY: Activation of the farnesoid X receptor (FXR) is a clinically validated approach for treating non-alcoholic steatohepatitis (NASH), although side effects such as itching or increases in low-density lipoprotein cholesterol are frequently dose-limiting. MET409, an FXR agonist with a unique chemical structure, led to significant liver fat reduction and delivered a favorable side effect profile after 12 weeks of treatment in patients with NASH. These results provide the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced.

Prevalencia de dislipidemias en la región capital: resultados preliminares del estudio EVESCAM / Prevalence of dyslipidemias in the capital region: preliminary results of the EVESCAM study

Las dislipidemias son un factor de riesgo para enfermedades cardiovasculares. Se desconoce la prevalencia actual de dislipidemias en la región Capital de Venezuela. Objetivo: Determinar la prevalencia de dislipidemias en adultos de la región capital evaluados en el estudio EVESCAM. Métodos: Estudio poblacional, observacional, transversal de muestreo aleatorio poliestratificado por conglomerados. Se evaluaron 7 comunidades de la Región Capital desde julio de 2015 hasta enero de 2016: El Retiro; Miranda Casco Central y Bello Campo; Los Teques: La Cima; Guatire: Centro y Castillejo y rural: Guatire: La Candelaria. Participaron 416 sujetos desde los 20 años de edad. Los puntos de corte para definir las dislipidemias fueron hipoalfalipoproteinemia: colesterol HDL < 40 mg/dL; hipertrigliceridemia: triglicéridos (TG) ≥ 150 mg/dL; hipercolesterolemia: colesterol total ≥ 200 mg/dL; colesterol LDL elevado: colesterol LDL ≥ de 130 mg/dL; dislipidemia aterogénica: TG ≥ 150 mg/dL más colesterol HDL bajo (mujeres: < 40 mg/dl y hombres: < 50 mg/dl). Las frecuencias se expresaron en porcentajes y se aplicó el estadístico Chi cuadrado, un valor de p < 0,05 fue considerado como estadísticamente significativo. Resultados: La dislipidemia con mayor prevalencia fue la hipoalfalipoproteinemia (67.1%) seguida de la LDLc elevada (20%), hipercolesterolemia (17,1%), hipertrigliceridemia (12,0%) y por último dislipidemia aterogenica (9,4%). La hipoalfalipoproteinemia, fue mayor en hombres que en mujeres (81,6% y 60,8%; respectivamente, p < 0,001) presentándose con mayor prevalencia en el grupo etario de 20 a 40 años al contrario del resto de las dislipidemias. Conclusión: La hipoalfalipoproteinemia persiste como la dislipidemia más prevalente de la región(AU)

Dyslipidemias are a risk factor for cardiovascular diseases. The current prevalence of dyslipidemias in the Capital Region of Venezuela is unknown. Objective: To determine the prevalence of dyslipidemias in adults from the capital region of Venezuela evaluated in the EVESCAM study. Methods: apopulation based, observational, cross-sectional, and cluster sampling study was desing. Seven communities from the Capital Region were evaluated from July 2015 to January 2016: El Retiro; Miranda- Chacao: Casco Central y Bello Campo; Los Teques: La Cima; Guatire: Centro y Castillejo y Rural: Guatire: Candelaria. 416 subjects were included. Dyslipidemias was define as hypoalphalipoproteinemia: HDL cholesterol <40 mg/ dL; hypertriglyceridemia: triglycerides ≥ 150 mg/dL; hypercholesterolemia: total cholesterol ≥ 200 mg/dL; High LDL cholesterol: ≥ 130 mg/dL; therogenic dyslipidemia: triglycerides ≥ 150 mg / dL and low HDL cholesterol (women: <40 mg / dl and men: <50 mg / dl). The frequencies were expressed as percentages and Chi-square test was applied to assess differences. The level of statistical significance accepted was a p-value < 0.05. Results: The most prevalent dyslipidemia was hypoalphalipoproteinemia (67.1%) followed by elevated LDLc (20%), hypercholesterolemia (17.1%), hypertriglyceridemia (12.0%), and atherogenic dyslipidemia (9.4%). Hypoalphalipoproteinemia was higher in men than women (81.6% and 60.8%, respectively, p <0.001), with a higher prevalence at the age group of 20 to 40 years, unlike the rest of dyslipidemias. Conclusion: The hypoalphalipoproteinemia persists as the most prevalent dyslipidemia in the region(AU)

[Blood fatty acids in the development and correction of metabolic syndrome]. / Zhirnye kisloty krovi v formirovanii i korrektsii metabolicheskogo sindroma.

AIM: to investigate the composition of plasma fatty acids (FA) and red blood cells and the level of eicosanoids in patients with metabolic syndrome (MS) and to assess whether metabolic disturbances may be corrected during a cycle use of an ω-3 polyunsaturated fatty acid (PUFA). SUBJECTS AND METHODS: Examinations were made in 46 patients, including Group 1 (a control group) of 15 persons without MS components; Group 2 of 31 patients with MS, Group 3 of 16 MS patients who had taken an ω-3 PUFA for 6 months, and Group 4 of 15 MS patients who had received the drug for 12 months. The composition of plasma FA and red blood cells was analyzed on a gas-liquid chromatograph. An enzyme immunoassay was used to measure the serum levels of tumor necrosis factor-α (TNF-α) and eicosanoids (thromboxane B2, 6-keto-prostaglandin F1α, leukotriene B4). A biologically active additive from the king crab (Paralithodes camtschatica) hepatopancreas was used as a source of ω-3 PUFA. RESULTS: Having a higher proportion of linoleic and α-linolenic acids in the plasma, the patients were found to have decreased levels of ω-3 and ω-6 PUFAs (linoleic and α-linolenic, arachidonic, and eicosapentaenoic acids) and a larger proportion of Mead acid and saturated FAs (myristic and stearic acids) in the red blood cells, suggesting that that cellular blood FA transfer was impaired and FAs were absorbed by cells. Their serum samples showed the high levels of leukotriene B4, 6-keto-prostaglandin F1α, and thromboxane A2. The long-term (6- and 12-month) use of ω-3 PUFA from the king crab hepatopancreas had a positive impact in modifying the lipid FA composition of red blood cells and in eliminating deficiencies of physiologically important ω-3 and ω-6 PUFAs in the blood cells. CONCLUSION: The findings suggest that FAs and their metabolites play an important role in the pathogenesis of MS and that dietary ω-3 PUFA should be incorporated into a package of preventive and therapeutic measures for MS.

Antilipogenic and anti-inflammatory activities of Codonopsis lanceolata in mice hepatic tissues after chronic ethanol feeding.

This study evaluated the antilipogenic and anti-inflammatory effects of Codonopsis lanceolata (C. lanceolata) root extract in mice with alcohol-induced fatty liver and elucidated its underlying molecular mechanisms. Ethanol was introduced into the liquid diet by mixing it with distilled water at 5% (wt/v), providing 36% of the energy, for nine weeks. Among the three different fractions prepared from the C. lanceolata root, the C. lanceolata methanol extract (CME) exhibited the most remarkable attenuation of alcohol-induced fatty liver with respect to various parameters such as hepatic free fatty acid concentration, body weight loss, and hepatic accumulations of triglyceride and cholesterol. The hepatic gene and protein expression levels were analysed via RT-PCR and Western blotting, respectively. CME feeding significantly restored the ethanol-induced downregulation of the adiponectin receptor (adipoR) 1 and of adipoR2, along with their downstream molecules. Furthermore, the study data showed that CME feeding dramatically reversed ethanol-induced hepatic upregulation of toll-like receptor- (TLR-) mediated signaling cascade molecules. These results indicate that the beneficial effects of CME against alcoholic fatty livers of mice appear to be with adenosine- and adiponectin-mediated regulation of hepatic steatosis and TLR-mediated modulation of hepatic proinflammatory responses.