PRMT3 inhibitor SGC707 reduces triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice

Protein arginine methyltransferase 3 (PRMT3) is a co-activator of liver X receptor capable of selectively modulating hepatic triglyceride synthesis. Here we investigated whether pharmacological PRMT3 inhibition can diminish the hepatic steatosis extent and lower plasma lipid levels and atherosclerosis susceptibility. Hereto, male hyperlipidemic low-density lipoprotein receptor knockout mice were fed an atherogenic Western-type diet and injected 3 times per week intraperitoneally with PRMT3 inhibitor SGC707 or solvent control. Three weeks into the study, SGC707-treated mice developed severe pruritus and scratching-associated skin lesions, leading to early study termination. SGC707-treated mice exhibited 50% lower liver triglyceride stores as well as 32% lower plasma triglyceride levels. Atherosclerotic lesions were virtually absent in all experimental mice. Plasma metabolite analysis revealed that levels of taurine-conjugated bile acids were ~ threefold increased (P < 0.001) in response to SGC707 treatment, which was paralleled by systemically higher bile acid receptor TGR5 signalling. In conclusion, we have shown that SGC707 treatment reduces hepatic steatosis and plasma triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice. These findings suggest that pharmacological PRMT3 inhibition can serve as therapeutic approach to treat non-alcoholic fatty liver disease and dyslipidemia/atherosclerosis, when unwanted effects on cholesterol and bile acid metabolism can be effectively tackled.

Ficus thonningii Stem Bark Extracts Prevent High Fructose Diet Induced Increased Plasma Triglyceride Concentration, Hepatic Steatosis and Inflammation in Growing Sprague-Dawley Rats

BACKGROUND: Ficus thonningii extracts exhibit hypoglycaemic, hypolipidaemic and antioxidant activities. We investigated the potential of methanolic F. thonningii stem-bark extracts (MEFT) to protect growing Sprague-Dawley (SD) against high-fructose diet-induced metabolic derangements (MD) in a model mimicking children fed obesogenic diets. METHODS: Eighty (40 males; 40 females) 21-days old SD rat pups were randomly allocat-ed to and administered, for 8 weeks, five treatment regimens: 1 - standard rat chow (SC) + water (PW), 2 - SC + 20% (w/v) fructose solution (FS), 3 - SC + FS + fenofibrate at 100 mg/kg bwt/day, 4 - SC + FS + low dose MEFT (LD; 50 mg/kg bwt/day) and 5 - SC + FS + high dose MEFT (HD; 500 mg/kg bwt/day). Body weight, glucose load tolerance, fasting blood glucose and triglyceride, plasma insulin concentration, sensitivity to insulin, liver mass and fat content, steatosis and inflammation were determined. RESULTS: Fructose had no effect on the rats&rsquo; growth, glucose and insulin concentration, glucose tolerance and insulin sensitivity (P&gt;0.05) but increased triglycerides in females; in-duced hepatic microsteatosis and inflammation in both sexes but macrosteatosis in females (P&lt;0.05). In females, MEFT prevented fructose-induced plasma triglyceride increase. Low dose MEFT increased liver lipid content in females (P&lt;0.05). The MEFT protected the rats against hepatic steatosis and inflammation but fenofibrate protected against hepatic mi-crosteatosis. CONCLUSION: MEFT can be used as prophylaxis against dietary fructose-induced ele-ments of MD but caution must be taken as low dose MEFT increases hepatic lipid accretion in females predisposing to fatty liver disease.

Fatty Acid-Inducible Part/ANGPTL4 Regulates Lipid Oxidation Response to Gelsemium Elegans Alkaloids

Background：The Gelsemium elegans alkaloids have been used in animal feed additives and already achieved terrific results in the pig’s gut health and weight gain. A series of studies have been conducted to explore the mechanisms by which it improves gut health and promotes growth. However, hardly any research has been done in the metabolic changes G. elegans alkaloids elicit in pork muscle. Angiopoietin-like 4 (ANGPTL4), an inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance, is transcribed at a higher rate relative to others in G. elegans alkaloids non-feeding muscle than in G. elegans alkaloids feeding muscle.Methods：A total of 24 muscle tissues and corresponding blood samples were collected from pigs and Target RNA was extracted using TRIzol reagent according to the manufacturer's instructions. Histological and immunofluorescence analysis combined with Western blot analysis were utilized to further explore the possible mechanism of ANGPTL4 and peroxisome proliferator-activated receptor-δ(PPARD).Results： This phenomenon results from that ANGPTL4 in G. elegans alkaloids non-feeding muscle is mediated by elevated plasma free fatty acids via PPARD, presumably leading to reduced local uptake of plasma triglyceride-derived fatty acids and their sparing for use by feeding with G. elegans alkaloids. In contrast, the transcription of ANGPTL4 in G. elegans alkaloids feeding muscle likely is counteracted via lipoprotein lipase(LPL)-mediated negative-regulation, promoting the use of plasma triglycerides as fuel for active muscles. Conclusion：The experimental result indicates that the muscle and the local regulation of ANGPTL4 via PPARD and LPL have critical roles in governing lipid homeostasis during the feeding process of pigs and will shed light on the molecular mechanism discovered by G. elegans alkaloids.

A Study of Atherogenic Plasma & Triglyceride-Glucose Indices and Monocyte/HDL-C Ratios in Colon Cancer Patients

Colon cancer is a tumor of the large intestine. It is the third most common cause of cancer-related death in the United States. However, most people with colon cancer get better if the cancer is found early. The atherogenic index of plasma (AIP), triglyceride-glucose (TyG) index, are strongly associated with atherogenesis of the coronary artery however, studies on its relationship with cancer are limited in the literature. This study aimed to investigate the association of the AIP, TyG index, and Monocyte/HDL-C with colon cancer patients.

Imbalanced Activation of Wnt-/β-Catenin-Signaling in Liver Endothelium Alters Normal Sinusoidal Differentiation

Endothelial wingless-related integration site (Wnt)-/β-catenin signaling is a key regulator of the tightly sealed blood–brain barrier. In the hepatic vascular niche angiokine-mediated Wnt signaling was recently identified as an important regulator of hepatocyte function, including the determination of final adult liver size, liver regeneration, and metabolic liver zonation. Within the hepatic vasculature, the liver sinusoidal endothelial cells (LSECs) are morphologically unique and functionally specialized microvascular endothelial cells (ECs). Pathological changes of LSECs are involved in chronic liver diseases, hepatocarcinogenesis, and liver metastasis. To comprehensively analyze the effects of endothelial Wnt-/β-catenin signaling in the liver, we used endothelial subtype-specific Clec4g-iCre mice to generate hepatic ECs with overexpression of Ctnnb1. In the resultant Clec4g-iCretg/wt;Ctnnb1(Ex3)fl/wt (Ctnnb1OE−EC) mice, activation of endothelial Wnt-/β-catenin signaling resulted in sinusoidal transdifferentiation with disturbed endothelial zonation, that is, loss of midzonal LSEC marker lymphatic vessel endothelial hyaluronic acid receptor 1 (Lyve1) and enrichment of continuous EC genes, such as cluster of differentiation (CD)34 and Apln. Notably, gene set enrichment analysis revealed overrepresentation of brain endothelial transcripts. Activation of endothelial Wnt-/β-catenin signaling did not induce liver fibrosis or alter metabolic liver zonation, but Ctnnb1OE−EC mice exhibited significantly increased plasma triglyceride concentrations, while liver lipid content was slightly reduced. Ctnnb1 overexpression in arterial ECs of the heart has been reported previously to cause cardiomyopathy. As Clec4g-iCre is active in a subset of cardiac ECs, it was not unexpected that Ctnnb1OE−EC mice showed reduced overall survival and cardiac dysfunction. Altogether, balanced endothelial Wnt-/β-catenin signaling in the liver is required for normal LSEC differentiation and for maintenance of normal plasma triglyceride levels.

Functional Status of Pancreatic α and β Cells in Type 2 Diabetes Mellitus Patients with Different Plasma Triglyceride Levels: A Retrospective Analysis

Objective. To investigate the functional status of pancreatic α and β cells in Type 2 diabetes mellitus (T2DM) patients with different plasma triglyceride (TG) levels. TG levels can be prognostic markers for T2DM. Methods. A total of 328 patients with T2DM were divided into three groups according to different TG levels: the TGL group: TG < 1.7 mmol/L; TGM group: 1.7 mmol/L ≤ TG < 2.3 mmol/L; and TGH group: TG ≥ 2.3 mmol/L. An oral glucose tolerance test (OGTT), insulin release test, and glucagon release test were performed in each patient. The changes of glucagon, glucagon/insulin ratio, early insulin secretion index ( Δ I 30 / Δ G 30 ), and area under the insulin curve (AUCI) were compared among each group. Also, the correlations between glucagon and pancreatic β-cell function, glycosylated hemoglobin (HbA1c), and other indices were analyzed. Results. With the increase of TG, the fasting and postprandial glucagon levels, the glucagon/insulin ratio, and the area under the glucagon curve (AUCG) presented an increasing trend. The homeostasis model assessment of insulin resistance (HOMA–IR) of the TGH group was significantly increased compared to the TGL and TGM groups. In addition to the increase in TG levels, the insulin sensitivity index (ISI), homeostasis model assessment for β-cell function index (HOMA-β), Δ I 30 / Δ G 30 , and AUCI displayed a reducing trend. Glucagon was negatively correlated with Δ I 30 / Δ G 30 , high-density lipoprotein (HDL), HOMA-β, body mass index (BMI), ISI, and AUCI ( P < 0.05 ) and positively correlated with fasting blood glucose (FPG), AUCG, HOMA-IR, HbA1c, duration, TG, low-density lipoprotein (LDL), and total cholesterol (TC) ( P < 0.05 ). Conclusion. Hypertriglyceridemia aggravated the dysfunction of pancreatic α and β cells. A reasonable control of the TG level makes it easier for blood glucose to reach the standard.

Chronic high fat feeding and prolonged fasting in liver-specific ANGPTL4 knockout mice

Obesity is associated with dyslipidemia, ectopic lipid deposition and insulin resistance. In mice, the global or adipose-specific loss of function of the protein angiopoietin-like 4 (ANGPTL4) leads to decreased plasma triglyceride levels, enhanced adipose triglyceride uptake, and protection from high-fat diet-induced glucose intolerance. ANGPTL4 is also expressed highly in the liver, but the role of liver-derived ANGPTL4 is unclear. The goal of this study was to determine the contribution of hepatocyte ANGPTL4 to triglyceride and glucose homeostasis in mice during a high fat diet challenge. We generated hepatocyte-specific ANGPTL4 deficient (Angptl4LivKO) mice, fed them a 60% kCal/fat diet (HFD) for 6 months, and assessed triglyceride, liver, and glucose metabolic phenotypes. We also explored the effects of prolonged fasting on Angptl4LivKO mice. The loss of hepatocyte-derived Angptl4 led to no major changes in triglyceride partitioning or lipoprotein lipase activity compared to control mice. Interestingly, although there was no difference in fasting plasma triglyceride levels after a 6 h fast, after an 18 h fast normal chow diet fed Angptl4LivKO mice had lower triglyceride levels than control mice. On a HFD, Angptl4LivKO mice initially showed no difference in glucose tolerance and insulin sensitivity, but improved glucose tolerance emerged in these mice after 6 months on HFD. Our data suggest that hepatocyte ANGPTL4 does not directly regulate triglyceride partitioning, but that loss of liver-derived ANGPTL4 may be protective from HFD-induced glucose intolerance and influence plasma TG metabolism during prolonged fasting.

The Role of Gut Microbiota and Its Produced Metabolites in Obesity, Dyslipidemia, Adipocyte Dysfunction, and Its Interventions

Obesity is becoming an increasing problem worldwide and is often, but not invariably, associated with dyslipidemia. The gut microbiota is increasingly linked to cardiovascular disease, nonalcoholic fatty liver disease, and type 2 diabetes mellitus. However, relatively little focus has been attributed to the role of gut-microbiota-derived metabolites in the development of dyslipidemia and alterations in lipid metabolism. In this review, we discuss current data involved in these processes and point out the therapeutic potentials. We cover the ability of gut microbiota metabolites to alter lipoprotein lipase action, VLDL secretion, and plasma triglyceride levels, and its effects on reverse cholesterol transport, adipocyte dysfunction, and adipose tissue inflammation. Finally, the current intervention strategies for treatment of obesity and dyslipidemia is addressed with emphasis on the role of gut microbiota metabolites and its ability to predict treatment efficacies.