Search

Intestinal lymphatic transport offers an alternative and effective way to deliver drugs, such as avoiding first-pass metabolism, enhancing oral bioavailability, and facilitating the treatment of targeted lymphoid-related diseases. However, the clinical use of luteolin (LUT) is limited by its poor water solubility and low bioavailability, and enhancing lymphatic transport by nanoemulsion may be an efficient way to enhance its oral bioavailability. The objective of this work is to prepare the luteolin nanoemulsions (LUT NEs), optimized its preparation parameters by using Box-Behnken design optimization (BBD) and evaluated it in vitro and in vivo. An Caco-2 / Raji B cell co-incubation monolayer model was established to simulate the M-cell pathway, and the differences in the transmembrane transport of LUT and NEs were compared. Cycloheximide (CHX) was utilized to establish rat chylomicron (CM) blocking model, and for investigating the influence of pharmacokinetic parameters in rats thereafter. The results showed that LUT NEs have good stability, the particle sizes were about 23.87 ± 0.57 nm. Compared with LUT suspension, The Papp of LUT NEs was enhanced for 3.5-folds, the oral bioavailability was increased by about 2.97-folds. In addition, after binding with chylomicron, the oral bioavailability of LUT NEs was decreased for about 30% (AUC 0–∞ (μg/L*h): 5.356 ± 1.144 vs 3.753 ± 0.188). These results demonstrated that NEs could enhance the oral absorption of luteolin via lymphatic transport routes. [ABSTRACT FROM AUTHOR]

Postprandial dyslipidemia is commonly present in people with type 2 diabetes and obesity and is characterized by overproduction of apolipoprotein B48-containing chylomicron particles from the intestine. Peripheral serotonin is emerging as a regulator of energy homeostasis with profound implications for obesity; however, its role in dietary fat absorption and chylomicron production is unknown. Chylomicron production was assessed in Syrian golden hamsters by administering an olive oil gavage and IP poloxamer to inhibit lipoprotein clearance. Administration of serotonin or selective serotonin reuptake inhibitor, fluoxetine, increased postprandial plasma triglyceride (TG) and TG-rich lipoproteins. Conversely, inhibiting serotonin synthesis pharmacologically by p-chlorophenylalanine (PCPA) led to a reduction in both the size and number of TG-rich lipoprotein particles, resulting in lower plasma TG and apolipoprotein B48 levels. The effects of PCPA occurred independently of gastric emptying and vagal afferent signaling. Inhibiting serotonin synthesis by PCPA led to increased TG within the intestinal lumen and elevated levels of TG and cholesterol in the stool when exposed to a high-fat/high-cholesterol diet. These findings imply compromised fat absorption, as evidenced by reduced lipase activity in the duodenum and lower levels of serum bile acids, which are indicative of intestinal bile acids. During the postprandial state, mRNA levels for serotonin receptors (5-HTRs) were upregulated in the proximal intestine. Administration of cisapride, a 5-HT4 receptor agonist, alleviated reductions in postprandial lipemia caused by serotonin synthesis inhibition, indicating that serotonin controls dietary fat absorption and chylomicron secretion via 5-HT4 receptor. [ABSTRACT FROM AUTHOR]

Lipid handling in the intestine is important for maintaining energy homeostasis and overall health. Mishandling of lipids in the intestine contributes to dyslipidemia and atherosclerotic cardiovascular diseases. Despite advances in this field over the past few decades, significant gaps remain. The gut hormone glucagon-like peptide-2 (GLP-2) has been shown to play pleotropic roles in the regulation of lipid handling in the intestine. Of note, GLP-2 exhibits unique actions on post-prandial lipid absorption and post-absorptive release of intestinally stored lipids. This review aims to summarize current knowledge in how GLP-2 regulates lipid processing in the intestine. Elucidating the mechanisms of GLP-2 regulation of intestinal lipid handling not only improves our understanding of GLP-2 biology, but also provides insights into how lipids are processed in the intestine, which offers opportunities for developing novel strategies towards prevention and treatment of dyslipidemia and atherosclerotic cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Since statins have had such tremendous therapeutic success over the last three decades, the field of atherosclerosis has become somewhat LDL-centric, dismissing the relevance of triglycerides (TG), particularly chylomicrons, in atherogenesis. Nonetheless, 50% of patients who take statins are at risk of developing atherosclerotic cardiovascular disease (ASCVD) and are unable to achieve their goal LDL-C levels. This residual risk is mediated, in part by triglyceride rich lipoproteins (TRL) and their remnants. Following his seminal investigation on the subject, Zilversmit proposed that atherosclerosis is a postprandial event in 1979 (1-4). In essence, the concept suggests that remnant cholesterol-rich chylomicron (CM) and very-low density lipoprotein (VLDL) particles play a role in atherogenesis. Given the foregoing, this narrative review addresses the most recent improvements in our understanding of postprandial dyslipidemia. The primary metabolic pathways of chylomicrons are discussed, emphasizing the critical physiological role of lipoprotein lipase and apoCIII, the importance of these particles' fluxes in the postprandial period, their catabolic rate, the complexities of testing postprandial metabolism, and the role of angiopoietin-like proteins in the partition of CM during the fed cycle. The narrative is rounded out by the dysregulation of postprandial lipid metabolism in insulin resistance states and consequent CVD risk, the clinical evaluation of postprandial dyslipidemia, current research limits, and potential future study directions. [ABSTRACT FROM AUTHOR]

Lipid handling in the intestine is important for maintaining energy homeostasis and overall health. Mishandling of lipids in the intestine contributes to dyslipidemia and atherosclerotic cardiovascular diseases. Despite advances in this field over the past few decades, significant gaps remain. The gut hormone glucagon-like peptide-2 (GLP-2) has been shown to play pleotropic roles in the regulation of lipid handling in the intestine. Of note, GLP-2 exhibits unique actions on post-prandial lipid absorption and post-absorptive release of intestinally stored lipids. This review aims to summarize current knowledge in how GLP-2 regulates lipid processing in the intestine. Elucidating the mechanisms of GLP-2 regulation of intestinal lipid handling not only improves our understanding of GLP-2 biology, but also provides insights into how lipids are processed in the intestine, which offers opportunities for developing novel strategies towards prevention and treatment of dyslipidemia and atherosclerotic cardiovascular diseases.

Since statins have had such tremendous therapeutic success over the last three decades, the field of atherosclerosis has become somewhat LDL-centric, dismissing the relevance of triglycerides (TG), particularly chylomicrons, in atherogenesis. Nonetheless, 50% of patients who take statins are at risk of developing atherosclerotic cardiovascular disease (ASCVD) and are unable to achieve their goal LDL-C levels. This residual risk is mediated, in part by triglyceride rich lipoproteins (TRL) and their remnants. Following his seminal investigation on the subject, Zilversmit proposed that atherosclerosis is a postprandial event in 1979 (1–4). In essence, the concept suggests that remnant cholesterol-rich chylomicron (CM) and very-low density lipoprotein (VLDL) particles play a role in atherogenesis. Given the foregoing, this narrative review addresses the most recent improvements in our understanding of postprandial dyslipidemia. The primary metabolic pathways of chylomicrons are discussed, emphasizing the critical physiological role of lipoprotein lipase and apoCIII, the importance of these particles’ fluxes in the postprandial period, their catabolic rate, the complexities of testing postprandial metabolism, and the role of angiopoietin-like proteins in the partition of CM during the fed cycle. The narrative is rounded out by the dysregulation of postprandial lipid metabolism in insulin resistance states and consequent CVD risk, the clinical evaluation of postprandial dyslipidemia, current research limits, and potential future study directions.

Larger intestinal lipoproteins are more likely to be retained longer in the intestinal wall, allowing more time for their fat to be hydrolyzed and subsequently taken up by the abdominal viscera. Since men generally accumulate more abdominal visceral fat than women, we sought to determine if males produce larger intestinal lipoproteins compared to females. Using the conscious lymph fistula mouse model, we discovered that the male mice indeed produced larger intestinal lipoproteins than the female mice when they were intraduodenally infused with lipid emulsion. We then employed our differentiated Caco-2 cell model with semipermeable membrane system to determine the effects of sex hormones on the size of intestinal lipoproteins. Lipoprotein size was quantitatively measured by calculating the ratio of triglycerides (TG)/Apolipoprotein B (ApoB) and by analyzing their transmission electron micrographs. Our studies showed that while there was no dose-dependent effect of estrogen and progesterone, testosterone significantly increased the size of lipoproteins. When these hormones were combined to resemble the physiological concentrations observed in males and the different ovarian cycle phases in premenopausal females, both the male and luteal groups had significantly larger lipoproteins than the ovulatory group; and the male group also had significantly larger lipoproteins than the follicular group. The ovulatory group secreted a significantly lower amount of TG than the male and luteal groups. ApoB was comparable among all these groups. These findings support our hypothesis that, through their testosterone effects, males are more likely to produce larger intestinal lipoproteins. Larger lipoproteins tend to remain longer in the intestinal wall and may facilitate fat uptake preferentially by the abdominal viscera. Our studies may partly explain why men are more prone to accumulating abdominal visceral fat, which is an independent predictor of mortality.

• Homozygosity for mutation Q384K in the APOB gene causes hypobetalipoproteinemia. • Mutation Q384K disrupts the structure of the large lipid transfer (LLT) module of apoB. • Secretion of apoB-100 from the liver was markedly reduced. • Secretion of apoB-48 from the intestine was normal. • Abnormal structure of LLT module affects lipidation of apoB-100. Molecular genetic testing of patients with hypobetalipoproteinemia may identify a genetic cause that can form the basis for starting proper therapy. Identifying a genetic cause may also provide novel data on the structure-function relationship of the mutant protein. To identify a genetic cause of hypobetalipoproteinemia in a patient with levels of low density lipoprotein cholesterol at the detection limit of 0.1 mmol/l. DNA sequencing of the translated exons with flanking intron sequences of the genes adenosine triphosphate-binding cassette transporter 1, angiopoietin-like protein 3, apolipoprotein B, apolipoprotein A1, lecithin-cholesterol acyltransferase, microsomal triglyceride transfer protein and proprotein convertase subtilisin/kexin type 9. The patient was homozygous for mutation Q384K (c.1150C>A) in the apolipoprotein B gene, and this mutation segregated with hypobetalipoproteinemia in the family. Residue Gln 384 is located in the large lipid transfer module of apoB that has been suggested to be important for lipidation of apolipoprotein B through interaction with microsomal triglyceride transfer protein. Based on measurements of serum levels of triglycerides and apolipoprotein B-48 after an oral fat load, we conclude that the patient was able to synthesize apolipoprotein B-48 in the intestine in a seemingly normal fashion. Our data indicate that mutation Q384K severely reduces the secretion of apolipoprotein B-100 in the liver without reducing the secretion of apolipoprotein B-48 in the intestine. Possible mechanisms for the different effects of this and other missense mutations affecting the large lipid transfer module on the two forms of apoB are discussed. [ABSTRACT FROM AUTHOR]

Chylomicrons, as the main source of intestinal triglyceride-rich lipoproteins and their remnants, can promote the occurrence and development of atherosclerosis. Therefore, reducing chylomicrons and their remnants are expected to be one of the effective methods to reduce the residual risk of cardiovascular disease. This review describes the key proteins in the production of chylomicrons and their molecular mechanisms, as well as the progress of Chinese and Western medicine therapy systematically in order to provide reliable new ideas for the prevention and treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]

Biallelic pathogenic variants of the Sar1b gene cause chylomicron retention disease (CRD) whose central phenotype is the inability to secrete chylomicrons. Patients with CRD experience numerous clinical symptoms such as gastrointestinal, hepatic, neuromuscular, ophthalmic, and cardiological abnormalities. Recently, the production of mice expressing either a targeted deletion or mutation of Sar1b recapitulated biochemical and gastrointestinal defects associated with CRD. The present study was conducted to better understand little-known aspects of Sar1b mutations, including mouse embryonic development, lipid profile, and lipoprotein composition in response to high-fat diet, gut and liver cholesterol metabolism, sex-specific effects, and genotype-phenotype differences. Sar1b deletion and mutation produce a lethal phenotype in homozygous mice, which display intestinal lipid accumulation without any gross morphological abnormalities. On high-fat diet, mutant mice exhibit more marked abnormalities in body composition, adipose tissue and liver weight, plasma cholesterol, non-HDL cholesterol and polyunsaturated fatty acids than those on the regular Chow diet. Divergences were also noted in lipoprotein lipid composition, lipid ratios (serving as indices of particle size) and lipoprotein-apolipoprotein distribution. Sar1b defects significantly reduce gut cholesterol accumulation while altering key players in cholesterol metabolism. Noteworthy, variations were observed between males and females, and between Sar1b deletion and mutation phenotypes. Overall, mutant animal findings reveal the importance of Sar1b in several biochemical, metabolic and developmental processes.

The regulation of cellular lipid storage and membrane lipid composition plays a critical role in metabolic homeostasis, and dysregulation may contribute to disorders such as obesity, fatty liver, type 2 diabetes, and cardiovascular disease. The mammalian lipin proteins (lipin 1, lipin 2, and lipin 3) are phosphatidic acid phosphatase (PAP) enzymes that modulate levels of cellular triacylglycerols and phospholipids, and also regulate lipid intermediates in cellular signaling pathways. Lipin proteins also have the ability to coactivate/corepress transcription. In humans and mice, lipin gene mutations cause severe metabolic phenotypes including rhabdomyolysis (lipin 1), autoinflammatory disease (lipin 2), and impaired intestinal lipoprotein assembly (lipin 2/lipin 3). Characterization of these diseases has revealed roles for lipin PAP activity in fundamental cellular processes such as autophagy, inflammasome activation, and lipoprotein assembly. Lipin protein activity is regulated at pre- and posttranscriptional levels, which suggests a need for their ordered response to specific physiological stimuli. Challenges for the future include better elucidation of the unique biochemical and physiological properties of individual lipin family members and determination of lipin protein structure-function relationships. Further research may propel exploration of lipin proteins as viable therapeutic targets in metabolic or inflammatory disorders.

The incidence of obesity and associated metabolic diseases is increasing globally, adversely affecting human health. Dietary fats, especially triglycerides, are an important source of energy for the body, and the intestine absorbs lipids through a series of orderly and complex steps. A long-term high-fat diet leads to intestinal dysfunction, inducing obesity and metabolic disorders. Therefore, regulating dietary triglycerides absorption is a promising therapeutic strategy. In this review, we will discuss diverse aspects of the dietary triglycerides hydrolysis, fatty acid uptake, triglycerides resynthesis, chylomicron assembly, trafficking, and secretion processes in intestinal epithelial cells, as well as potential targets in this process that may influence dietary fat-induced obesity and metabolic diseases. We also mention the possible shortcomings and deficiencies in modulating dietary lipid absorption targets to provide a better understanding of their administrability as drugs in obesity and related metabolic disorders. [ABSTRACT FROM AUTHOR]

• Triglyceride assay, indirect marker of the presence of chylomicrons, is the most common first-line biochemical test for determining the chylous nature of various effusion such as chylous ascite, chylothorax or chylopericardium. • apoB48 is a trafficking handle and a direct biomarker for chylomicrons. • Simple, rapid apoB48 immunoassay can be of value (relative to the gold-standard test, gel lipoprotein electrophoresis) in the diagnosis of chylous effusions of origin. Chylous effusions such as chylothorax, chylopericardium and chylous ascites are marked by the abnormal presence of chylomicrons in serous membranes. These relatively rare situations are associated with high morbidity and mortality rates. Given that a macroscopic assessment of the fluid is insufficient, the current gold standard method for chylous effusion is the electrophoretic separation of lipoproteins. Serous effusions are most frequently assayed for triglycerides, with a diagnostic threshold varying between studies. The present study is the first to assess the value of the apolipoprotein B48, specific of the chylomicron, in the diagnosis of chylous effusions. A chemiluminescent sandwich enzyme immunoassay was used to measure levels of apoB48 in remnant samples of effusion fluid sent to our laboratory for chylomicron detection and lipid assays. The diagnostic values of apoB48 and triglyceride assays were compared with that of the gold standard method. The triglyceride and apoB48 levels and the triglyceride/cholesterol ratio in the effusion fluid were significantly higher in patients with chylous effusion. The threshold values for apoB48 were respectively 2.45, 0.25 and 19.00 µg/mL for a maximal Youden index, a sensitivity > 95 %, and a specificity > 95 %. The apoB48 assay's diagnostic value might be at least as high as that of a triglyceride assay (area under the receiver operating characteristic curve [95 % confidence interval]: 0.84 [0.72, 0.96]) and 0.80 [0.67, 0.94], respectively). ApoB48 appears to be a promising marker for the diagnosis of chylous effusions; the putative diagnostic improvement must be confirmed in larger studies. [ABSTRACT FROM AUTHOR]

Nutrient digestion, absorption, and export must be coordinated in the gut to meet the nutritional needs of the organism. We used the Drosophila intestine to characterize the mechanisms that coordinate the fate of dietary lipids. We identified enterocytes specialized in absorbing and exporting lipids to peripheral organs. Distinct hepatocyte-like cells, called oenocytes, communicate with these enterocytes to adjust intestinal lipid storage and export. A single transcription factor, Drosophila hepatocyte nuclear factor 4 (dHNF4), supports this gut-liver axis. In enterocytes, dHNF4 maximizes dietary lipid export by preventing their sequestration in cytoplasmic lipid droplets. In oenocytes, dHNF4 promotes the expression of the insulin antagonist ImpL2 to activate Foxo and suppress lipid retention in enterocytes. Disruption of this switch between lipid storage and export is associated with intestinal inflammation, suggesting a lipidic origin for inflammatory bowel diseases. These studies establish dHNF4 as a central regulator of intestinal metabolism and inter-organ lipid trafficking. [Display omitted] • Specific enterocyte populations absorb dietary lipids in the Drosophila intestine • Enterocyte lipid storage and export are remotely controlled by oenocytes • Drosophila HNF4 acts in both cell types to regulate inter-organ lipid trafficking • Abnormal lipid storage in the intestine induces local inflammation Vonolfen et al. show that Drosophila hepatocyte nuclear factor 4 acts in enterocytes and oenocytes to coordinate intestinal lipid storage and export. These regulations suppress intestinal steatosis while maintaining body fat levels. They also suppress manifestations of inflammatory bowel diseases, suggesting links between these intestinal disorders and impaired lipid export. [ABSTRACT FROM AUTHOR]

A portion of absorbed dietary triglycerides (TG) is retained in the intestine after the postprandial period, within intracellular and extracellular compartments. This pool of TG can be mobilized in response to several stimuli, including oral glucose. The objective of this study was to determine whether oral glucose must be absorbed and metabolized to mobilize TG in rats and whether high-fat feeding, a model of insulin resistance, alters the lipid mobilization response to glucose. Lymph flow, TG concentration, TG output, and apolipoprotein B48 (apoB48) concentration and output were assessed after an intraduodenal lipid bolus in rats exposed to the following intraduodenal administrations 5 h later: saline (placebo), glucose, 2-deoxyglucose (2-DG, absorbed but not metabolized), or glucose + phlorizin (intestinal glucose absorption inhibitor). Glucose alone, but not 2-DG or glucose þ phlorizin treatments, stimulated lymph flow, TG output, and apoB48 output compared with placebo. The effects of glucose in high-fat-fed rats were similar to those in chow-fed rats. In conclusion, glucose must be both absorbed and metabolized to enhance lymph flow and intestinal lipid mobilization. This effect is qualitatively and quantitatively similar in high-fat- and chowfed rats. The precise signaling mechanism whereby enteral glucose enhances lymph flow and mobilizes enteral lipid remains to be determined. NEW & NOTEWORTHY Glucose potently enhances mesenteric lymph flow in chow- and high-fat-fed rats. The magnitude of glucose effect on lymph flow is no different in chow- and high-fat-fed rats. Glucose must be absorbed and metabolized to enhance lymph flow and mobilize intestinal lipid. [ABSTRACT FROM AUTHOR]

Postprandial hyperlipidaemia is an important feature of diabetic dyslipidaemia and plays an important role in the development of cardiovascular disease in individuals with type 2 diabetes. Postprandial hyperlipidaemia in type 2 diabetes is secondary to increased chylomicron production by the enterocytes and delayed catabolism of chylomicrons and chylomicron remnants. Insulin and some intestinal hormones (e.g. glucagon-like peptide-1 [GLP-1]) influence intestinal lipid metabolism. In individuals with type 2 diabetes, insulin resistance and possibly reduced GLP-1 secretion are involved in the pathophysiology of postprandial hyperlipidaemia. Several factors are involved in the overproduction of chylomicrons: (1) increased expression of microsomal triglyceride transfer protein, which is a key enzyme in chylomicron synthesis; (2) higher stability and availability of apolipoprotein B-48; and (3) increased de novo lipogenesis. Individuals with type 2 diabetes present with disorders of cholesterol metabolism in the enterocytes with reduced absorption and increased synthesis. The increased production of chylomicrons in type 2 diabetes is also associated with a reduction in their catabolism, mostly because of a reduction in activity of lipoprotein lipase. Modification of the microbiota, which is observed in type 2 diabetes, may also generate disorders of intestinal lipid metabolism, but human data remain limited. Some glucose-lowering treatments significantly influence intestinal lipid absorption and transport. Postprandial hyperlipidaemia is reduced by metformin, pioglitazone, alpha-glucosidase inhibitors, dipeptidyl peptidase 4 inhibitors and GLP-1 agonists. The most pronounced effect is observed with GLP-1 agonists, which reduce chylomicron production significantly in individuals with type 2 diabetes and have a direct effect on the intestine by reducing the expression of genes involved in intestinal lipoprotein metabolism. The effect of sodium–glucose cotransporter 2 inhibitors on intestinal lipid metabolism needs to be clarified. [ABSTRACT FROM AUTHOR]

Innovative medical education greatly relies on lifelong learning with universal standards in research, for generating novel knowledge for improvement maximum patient care. The other side of innovative medical education relies on success of development of novel ideas, perspective; skill building, future career objectives. Leaders have curious roles in the research assistant education. In the current century, both technology and education raced forward in many countries. Mobbing and bullying is an important problem in all fields, every sphere of life in workplaces. Unethical behavior must not take place in universities because universities are the centers of learning, and best academic teaching in ethical standards. Bullying may damage every individual in every academic degree and effect academic performance. In this paper I will discuss a mobbing case which is done to a young academician in many years ago, which is not most frequently observed type. However, such bullying behaviors may increase due to COVID-19 pandemic. Because COVID-19 pandemic may cause various problems in social groups difficulties, anxiety, and economic challenges, problems. Nowadays everybody is experiencing worry, uncertainty, anxiety, fear of economic problems, fear of dying. COVID-19 pandemic has created some unexpected problems to everybody however, academic researchers have additional worries and fears such as; the expiration time of chemicals, problems on chemicals are not imported from abroad on time also difficulties of knockout or transgenic experimental animals cannot be imported from abroad on time, and all these problems cause fear of unsuccessful experimental results, spending extra time. All these anxieties may cause arouse increasing unstable friendships and mobbing possibilities. The COVID-19 disease takes our future and experimental plans to waste basket and change everything including friendship. [ABSTRACT FROM AUTHOR]

Practicing endocrinologists are likely to confront 2 major issues that occur with dyslipidemias during pregnancy. The most dramatic is the development of severe hypertriglyceridemia leading to acute pancreatitis. The second is the approach to treatment of familial hypercholesterolemia, a common genetic disorder. This article reviews the normal physiology and the pathophysiology of lipoproteins that occurs with pregnancy and then discusses the approaches to prevention and/or treatment of dyslipidemia in pregnancy with a focus on lifestyle and acceptable drug therapies., Competing Interests: Disclosure Dr I.J. Goldberg has received consulting fees from Arrowhead, Mammoth, and LG Pharmaceutical., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background/Objective: GLP-1R agonists have been shown to reduce fasting and postprandial plasma lipids, both of which are independent risk factors for the development of cardiovascular disease. However, how endogenous GLP-1 – which is rapidly degraded – modulates intestinal and hepatic lipid metabolism is less clear. A vagal gut-brain-axis originating in the portal vein has been proposed as a possible mechanism for GLP-1’s anti-lipemic effects. Here we sought to examine the relationship between vagal GLP-1 signalling and intestinal lipid absorption and lipoprotein production. Methods: Syrian golden hamsters or C57BL/6 mice received portal vein injections of GLP-1(7-36), and postprandial and fasting plasma TG, TRL TG, or VLDL TG were examined. These experiments were repeated during sympathetic blockade, and under a variety of pharmacological or surgical deafferentation techniques. In addition, hamsters received nodose ganglia injections of a GLP-1R agonist or antagonist to further probe the vagal pathway. Peripheral studies were repeated in a novel GLP-1R KO hamster model and in our diet-induced hamster models of insulin resistance. Results: GLP-1(7-36) site-specifically reduced postprandial and fasting plasma lipids in both hamsters and mice. These inhibitory effects of GLP-1 were investigated via pharmacological and surgical denervation experiments and found to be dependent on intact afferent vagal signalling cascades and efferent changes in sympathetic tone. Furthermore, GLP-1R agonism in the nodose ganglia resulted in markedly reduced postprandial plasma TG and TRL TG, and fasting VLDL TG and this nodose GLP-1R activity was essential for portal GLP-1s effect. Notably, portal and nodose ganglia GLP-1 effects were lost in GLP-1R KO hamsters and following diet-induced insulin resistance. Conclusion: Our data demonstrates for the first time that portal GLP-1 modulates postprandial and fasting lipids via a complex vagal gut–brain–liver axis. Importantly, loss or interference with this signalling axis via surgical, pharmacological, or dietary intervention resulted in the loss of portal GLP-1s anti-lipemic effects. This supports emerging evidence that native GLP-1 works primarily through a vagal neuroendocrine mechanism.

Lipids are considered as organic substances that are relatively insoluble in water while soluble in organic solvents such as alcohol and ether. Unlike carbohydrates, proteins and nucleic acids, lipids are not polymers. Further, lipids are mostly small molecules. More than 90% of the fatty acids found in plasma are in the form of fatty acid esters primarily in the form of triacylglycerol, cholesteryl esters. Lipids can be exogenously from the dietary sources and endogenously mainly from the liver. Due to insolubility of lipids, so the circulation of lipids in the blood is performed by the actions of several transport vehicles such as spherical protein complexes which is known as lipoproteins which is an assembly of lipids with proteins. There are four major types of lipoproteins are participating in transporting lipids in plasma, which are classified based on their density, these includes chylomicrons (CM), very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Different types of lipoproteins have a different set of proteins (apoprotein) on their surface, these proteins served as address tags that determine both destination and function of each lipoprotein. In this review, we summarise the pathways and metabolites that involve in lipid and lipoprotein metabolism.

Orally administered drug entities have to survive the harsh gastrointestinal environment, penetrate the enteric epithelia and circumvent hepatic metabolism before reaching the systemic circulation. Whereas the gastrointestinal stability can be well maintained by taking proper measures, hepatic metabolism presents as a formidable barrier to drugs suffering from first-pass metabolism. The pharmaceutical academia and industries are seeking alternative pathways for drug transport to circumvent problems associated with the portal pathway. Intestinal lymphatic transport is emerging as a promising pathway to this end. In this review, we intend to provide an updated overview on the rationale, strategies, factors and applications involved in intestinal lymphatic transport. There are mainly two pathways for peroral lymphatic transport—the chylomicron and the microfold cell pathways. The underlying mechanisms are being unraveled gradually and nowadays witness increasing research input and applications.

Abstract Lipids are the most energy‐dense components of the diet, and their overconsumption promotes obesity and diabetes. Dietary fat content has been linked to the lipid processing activity by the intestine and its overall capacity to absorb triglycerides (TG). However, the signaling cascades driving intestinal lipid absorption in response to elevated dietary fat are largely unknown. Here, we describe an unexpected role of the protein kinase D2 (PKD2) in lipid homeostasis. We demonstrate that PKD2 activity promotes chylomicron‐mediated TG transfer in enterocytes. PKD2 increases chylomicron size to enhance the TG secretion on the basolateral side of the mouse and human enterocytes, which is associated with decreased abundance of APOA4. PKD2 activation in intestine also correlates positively with circulating TG in obese human patients. Importantly, deletion, inactivation, or inhibition of PKD2 ameliorates high‐fat diet‐induced obesity and diabetes and improves gut microbiota profile in mice. Taken together, our findings suggest that PKD2 represents a key signaling node promoting dietary fat absorption and may serve as an attractive target for the treatment of obesity.

In mammals, physiological processes related to lipid metabolism, such as chylomicron synthesis or fatty acid oxidation (FAO), modulate eating, highlighting the importance of energostatic mechanisms in feeding control. This study, using rainbow trout (Oncorhynchus mykiss) as model, aimed to characterize the role of FAO and chylomicron formation as peripheral lipid sensors potentially able to modulate feeding in fish. Fish fed with either a normal- (24%) or high- (32%) fat diet were intraperitoneally injected with water alone or containing etomoxir (inhibitor of FAO rate-limiting enzyme carnitine palmitoyl-transferase 1). First, feed intake levels were recorded. We observed an etomoxir-derived decrease in feeding at short times, but a significant increase at 48 h after treatment in fish fed normal-fat diet. Then, we evaluated putative etomoxir effects on the mRNA abundance of genes related to lipid metabolism, chylomicron synthesis and appetite-regulating peptides. Etomoxir treatment upregulated mRNA levels of genes related to chylomicron assembly in proximal intestine, while opposite effects occurred in distal intestine, indicating a clear regionalization in response. Etomoxir also modulated gastrointestinal hormone mRNAs in proximal intestine, upregulating ghrl in fish fed normal-fat diet and pyy and gcg in fish fed high-fat diet. These results provide evidence for an energostatic control of feeding related to FAO and chylomicron formation at the peripheral level in fish. [Display omitted] • High-fat diet did not produce changes in feed intake in rainbow trout. • Generally, etomoxir did inhibit Cpt1 activity in fish and modified feed intake. • The results highlight the existence of an energostatic control of eating in fish. • Fat affects differentially to chylomicron assembly depending on intestinal region. [ABSTRACT FROM AUTHOR]

Oluwayemisi Esan, Anthony S Wierzbicki Department of Metabolic Medicine/Chemical Pathology, Guy’s & St Thomas’ Hospitals, London SE1 7EH, UKCorrespondence: Anthony S WierzbickiDepartment of Chemical Pathology, St. Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, UKTel +0207 188 1256Fax +0207 188 7325Email anthony.wierzbicki@kcl.ac.ukAbstract: Severe hypertriglyceridaemia is associated with pancreatitis and chronic pancreatitis-induced diabetes. Familial chylomicronaemia syndrome (FCS) is a rare autosomal recessive disorder of lipid metabolism characterised by high levels of triglycerides (TGs) due to failure of chylomicron clearance. It causes repeated episodes of severe abdominal pain, fatigue and attacks of acute pancreatitis. There are few current options for its long-term management. The only universal long-term therapy is restriction of total dietary fat intake to < 10-15% of daily calories (15 to 20g per day). Many patients have been treated with fibrates and statins with a variable response, but many remain susceptible to pancreatitis. Other genetic syndromes associated with hypertriglyceridaemia include familial partial lipodystrophy (FPLD). Targeting apolipoprotein C3 (apoC3) offers the ability to increase clearance of chylomicrons and other triglyceride-rich lipoproteins. Volanesorsen is an antisense oligonucleotide (ASO) inhibitor of apoC3, which reduces TG levels by 70– 80% which has been shown also to reduce rates of pancreatitis and improve well-being in FCS and reduce TGs and improve insulin resistance in FPLD. It is now undergoing licensing and payer reviews. Further developments of antisense technology including small interfering RNA therapy to apoC3 as well as other approaches to modulating triglycerides are in development for this rare disorder.Keywords: triglyceride, pancreatitis, familial chylomicronaemia syndrome, lipoprotein lipase, chylomicron, lipodystrophy, familial partial lipodystrophy, volanesorsen

Abstract Background Apolipoprotein CIII (apoCIII) is associated with triglyceride-rich lipoprotein metabolism and has emerged as independent marker for risk of cardiovascular disease. The objective was to test whether apoCIII is regulated postprandially and whether apoCIII concentrations in native and chylomicron-free serum predict future cardiovascular events in patients with stable coronary artery disease (CAD). Methods ApoCIII concentrations were measured in native and chylomicron-free serum in the fasting state and after a standardized oral fat load test in 195 patients with stable CAD. Clinical follow-up was 48 months. Chylomicron-free serum was prepared by ultracentrifugation (18,000 rpm, 3 h). The log-rank test and Cox regression analyses were used to investigate the association of apoCIII with recurrent cardiovascular events. Results Of the 195 patients included, 92 had a cardiovascular event, and 103 did not. 97% were treated with a statin. No significant changes in apoCIII concentration were observed after the oral fat load test. The apoCIII concentration was associated with event-free survival independent of conventional risk factors. This association reached statistical significance only for apoCIII concentration measured in chylomicron-free serum (hazard ratio [95% confidence interval] for apoCIII above the mean: postprandial: 1.67 (1.06–2.29), P = 0.028, fasting: 2.09 (1.32–3.32), P = 0.002), but not for apoCIII concentration measured in native serum (postprandial: 1.47 [0.89–2.43], P = 0.133, fasting: 1.56 [0.95–2.58], P = 0.081). The effects were independent of other risk factors. Conclusions ApoCIII concentrations in chylomicron-free serum are independently associated with event-free survival in patients with CAD both in fasting and postprandial state. This findings support considering apoCIII for risk assessment and attempting to test the hypothesis that lowering apoCIII reduces residual cardiovascular risk. Take home message Apolipoprotein CIII concentration measured in chylomicron-free serum predicts recurrent cardiovascular events in patients with stable coronary artery disease. Trial registration The trial which included the participants of this study was registered at https://clinicaltrials.gov ( NCT00628524 ) on March 5, 2008.

There is a great progress in understanding the cellular and molecular aspects of atherosclerosis, which is one of the leading causes of death. Yet, there are questions regarding the cellular and metabolic mechanisms that lead to atherogenesis. Among the many factors that influence this process, food plays a significant role. Among other factors that play a paramount role in atherogensis are alterations of the transport of food in enterocytes, oxysterols, development of an atherogenic serum, endothelial damage, accumulation of foam cells within the vessel wall, lysosome-ER transport, and hypertension. Here, we discuss the contribution of secretion, transcytosis, endocytosis of chylomicrons, low-density lipoproteins (LDL), very LDL, and high-density lipoproteins to atherogenesis.

Background: The genetic substrate of severe hypertriglyceridemia (sHTG) in Latin America is insufficiently understood., Objective: To identify genetic variants in genes related to triglyceride (TG) metabolism among adults with sHTG from Colombia., Methods: In individuals with plasma TG≥880 mg/dL at least once in their lifetime, we amplified and sequenced all exons and intron/exon boundaries of the genes LPL, APOC2, APOA5, GPIHBP1 and LMF1. For each variant we ascertained its location, zygosity, allelic frequency and pathogenicity classification according to American College of Medical Genetics (ACMG) criteria., Results: The study included 166 participants (62 % male, mean age 50), peak TG levels ranged between 894 and 11,000 mg/dL. We identified 92 variants: 19 in LPL, 7 in APOC2, 11 in GPIHBP1, 38 in LMF1, and 17 in APOA5. Eighteen of these variants had not been reported. We identified a new pathogenic variant in LMF1 (c.41C>A; p.Ser14*), a new likely pathogenic variant in LMF1 (c.1527 C > T; p.Pro509=, also expressed as c.1447C>T; p.Gln483*), and a known pathogenic variant in LMF1 (c.779G>A; p.Trp260*). Four participants were heterozygous for variant c.953A>G; p.Asn318Ser in LPL, a known risk factor for hypertriglyceridemia. Participants with variants of unknown significance (VUS) in LMF1 had significantly higher peak TG than those with VUS in other genes. Peak TG were 4317 mg/dL in participants with a history of pancreatitis, and 1769 mg/dL in those without it (p = 0.001)., Conclusion: Our study identified variants associated with sHTG among Latinos, and showed that genetic variation in LMF1 may be frequently associated with sHTG in this population., Competing Interests: Declaration of competing interest This study was funded by PTC Therapeutics through an investigator-initiated grant, but the sponsor had no incidence in the design or execution of the study, or on the decision to publish., (Copyright © 2024. Published by Elsevier Inc.)

Background: Breast cancer survivors are a growing population due to improved treatment. It is known that postmenopausal women treated for breast cancer may experience weight gain and increased insulin resistance, but detailed knowledge on how chemotherapy impact metabolic and endocrine mechanisms remain unknown., Objectives: We performed a thorough, preliminary study to elucidate the differing mechanisms of postprandial absorption and metabolism in postmenopausal early breast cancer (EBC) patients treated with adjuvant chemotherapy compared to healthy controls. We hypothesize that chemotherapy has a negative impact on metabolism in EBC patients., Methods: We examined four postmenopausal women shortly after treatment with chemotherapy for EBC and four age-matched healthy women who served as controls using isotopic tracers during a mixed meal-test. Blood was sampled during the 240 min meal-test to examine postprandial absorption and endogenous synthesis of lipid and carbohydrate metabolites., Results: We found that insulin concentrations were numerically higher before the meal-test in the EBC patients compared to controls (76.3 pmol/L vs 37.0 pmol/L; P = 0.06). Glucose kinetics was increased postprandial (most pronounced at 30 min, 9.46 mmol/L vs 7.33 mmol/L; P = 0.51), with no difference between the groups regarding liver glucose output. Fatty acid kinetics showed a numeric increase in oleic acid rate of appearance in BC patients, but only during the first hour after the mixed meal. There was no significant difference in VLDL-TAG synthesis between the two groups., Conclusions: This preliminary study is unique in using advanced tracer methods to investigate in vivo metabolism of EBC patients after chemotherapy although no statistical differences in glucose and fatty acid kinetics was seen compared to controls. However, during the first two postprandial hours, oral glucose and oleic acid appearance in the systematic circulation was elevated in the EBC patients. This could be due to changes in gastrointestinal uptake and further studies with altered set-up could provide valuable insights., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Peter Schwarz reports financial support was provided by Greater Copenhagen Research Foundation. Peter Schwarz reports financial support was provided by MD Sofus Carl Emil and wife Olga Friis Scholarship. Linn Gillberg reports financial support was provided by Novo Nordisk Foundation. Linn Gillberg reports financial support was provided by The Danish Diabetes and Endocrine Academy. Gerrit van Hall reports financial support was provided by Arla Food for Health initiative. Peter Schwarz reports financial support was provided by Svend Andersen Fonden og Aase og Ejnar Danielsens Fond., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Orally administered drug entities have to survive the harsh gastrointestinal environment, penetrate the enteric epithelia and circumvent hepatic metabolism before reaching the systemic circulation. Whereas the gastrointestinal stability can be well maintained by taking proper measures, hepatic metabolism presents as a formidable barrier to drugs suffering from first-pass metabolism. The pharmaceutical academia and industries are seeking alternative pathways for drug transport to circumvent problems associated with the portal pathway. Intestinal lymphatic transport is emerging as a promising pathway to this end. In this review, we intend to provide an updated overview on the rationale, strategies, factors and applications involved in intestinal lymphatic transport. There are mainly two pathways for peroral lymphatic transport—the chylomicron and the microfold cell pathways. The underlying mechanisms are being unraveled gradually and nowadays witness increasing research input and applications. Orally administered molecular drugs and particulates could be absorbed alternatively via lymphatic transport. There are two main pathways—the chylomicron and M cell pathway—for efficient lymphatic transport. [Display omitted] [ABSTRACT FROM AUTHOR]

Lipids are the most energy‐dense components of the diet, and their overconsumption promotes obesity and diabetes. Dietary fat content has been linked to the lipid processing activity by the intestine and its overall capacity to absorb triglycerides (TG). However, the signaling cascades driving intestinal lipid absorption in response to elevated dietary fat are largely unknown. Here, we describe an unexpected role of the protein kinase D2 (PKD2) in lipid homeostasis. We demonstrate that PKD2 activity promotes chylomicron‐mediated TG transfer in enterocytes. PKD2 increases chylomicron size to enhance the TG secretion on the basolateral side of the mouse and human enterocytes, which is associated with decreased abundance of APOA4. PKD2 activation in intestine also correlates positively with circulating TG in obese human patients. Importantly, deletion, inactivation, or inhibition of PKD2 ameliorates high‐fat diet‐induced obesity and diabetes and improves gut microbiota profile in mice. Taken together, our findings suggest that PKD2 represents a key signaling node promoting dietary fat absorption and may serve as an attractive target for the treatment of obesity. Synopsis: We show that upon fat ingestion, Protein Kinase D2 stimulates chylomicron‐mediated triglyceride absorption in the intestine. Targeting PKD2, genetically or with small molecule inhibitors, reduces triglycerides absorption and prevents the development of obesity in mice and presumably in humans. PKD2 enhances chylomicron size and therefore chylomicron‐mediated triglycerides absorption.PKD2 phosphorylates chylomicron‐associated lipoprotein, APOA4.Inhibition of PKD2 diminishes obesity and associated diabetes.PKD2 activity correlates with triglycerides levels in obese patients. [ABSTRACT FROM AUTHOR]

During the last two decades, a large body of information on the events responsible for intestinal fat digestion and absorption has been accumulated. In particular, many groups have extensively focused on the absorptive phase in order to highlight the critical “players” and the main mechanisms orchestrating the assembly and secretion of chylomicrons (CM) as essential vehicles of alimentary lipids. The major aim of this article is to review understanding derived from basic science and clinical conditions associated with impaired packaging and export of CM. We have particularly insisted on inborn metabolic pathways in humans as well as on genetically modified animal models (recapitulating pathological features). The ultimate goal of this approach is that “experiments of nature” and in vivo model strategy collectively allow gaining novel mechanistic insight and filling the gap between the underlying genetic defect and the apparent clinical phenotype. Thus, uncovering the cause of disease contributes not only to understanding normal physiologic pathway, but also to capturing disorder onset, progression, treatment and prognosis.

Chylomicron retention disease (CRD) is an autosomal recessive disorder associated with biallelic Sar1b mutations leading to defects in intracellular chylomicron (CM) trafficking and secretion. To date, a direct cause-effect relationship between CRD and Sar1b mutation has not been established, but genetically modified animal models provide an opportunity to elucidate unrecognized aspects of these mutations. To examine the physiological role and molecular mechanisms of Sar1b function, we generated mice expressing either a targeted deletion or mutation of human Sar1b using the CRISPR-Cas9 system. We found that deletion or mutation of Sar1b in mice resulted in late-gestation lethality of homozygous embryos. Moreover, compared with WT mice, heterozygotes carrying a single disrupted Sar1b allele displayed lower plasma levels of triglycerides, total cholesterol, and HDL-cholesterol, along with reduced CM secretion following gastric lipid gavage. Similarly, decreased expression of apolipoprotein B and microsomal triglyceride transfer protein was observed in correlation with the accumulation of mucosal lipids. Inefficient fat absorption in heterozygotes was confirmed via an increase in fecal lipid excretion. Furthermore, genetically modified Sar1b affected intestinal lipid homeostasis as demonstrated by enhanced fatty acid β-oxidation and diminished lipogenesis through the modulation of transcription factors. This is the first reported mammalian animal model with human Sar1b genetic defects, which reproduces some of the characteristic CRD features and provides a direct cause-effect demonstration.

During the last two decades, a large body of information on the events responsible for intestinal fat digestion and absorption has been accumulated. In particular, many groups have extensively focused on the absorptive phase in order to highlight the critical "players" and the main mechanisms orchestrating the assembly and secretion of chylomicrons (CM) as essential vehicles of alimentary lipids. The major aim of this article is to review understanding derived from basic science and clinical conditions associated with impaired packaging and export of CM. We have particularly insisted on inborn metabolic pathways in humans as well as on genetically modified animal models (recapitulating pathological features). The ultimate goal of this approach is that "experiments of nature" and in vivo model strategy collectively allow gaining novel mechanistic insight and filling the gap between the underlying genetic defect and the apparent clinical phenotype. Thus, uncovering the cause of disease contributes not only to understanding normal physiologic pathway, but also to capturing disorder onset, progression, treatment and prognosis. [ABSTRACT FROM AUTHOR]

Fatty meals induce intestinal secretion of chylomicrons (CMs) containing apolipoprotein (Apo) B48. These CMs travel via the lymphatic system before entering the circulation. ApoB48 is produced after post-transcriptional RNA modification by Apobec-1 editing enzyme, exclusively in the small intestine of humans and most other mammals. In contrast, in the liver where Apobec-1 editing enzyme is not expressed (except in rats and mice), the unedited transcript encodes a larger protein, ApoB100, which is used in the formation of very low-density lipoproteins (VLDL) to transport liver-synthesized fat to peripheral tissues. Apobec-1 knockout (KO) mice lack the ability to perform ApoB RNA editing, and thus, express ApoB100 in the intestine. These mice, maintained on either a chow diet or high fat diet, have body weight gain and food intake comparable to their wildtype (WT) counterparts on the respective diet; however, they secrete larger triglyceride (TG)-rich lipoprotein particles and at a slower rate than the WT mice. Using a lymph fistula model, we demonstrated that Apobec-1 KO mice also produced fewer CMs and exhibited reduced lymphatic transport of TG in response to duodenal infusion of TG at a moderate dose; in contrast, the Apobec-1 KO and WT mice had similar lymphatic transport of TG when they received a high dose of TG. Thus, the smaller, energy-saving ApoB48 appears to play a superior role in comparison with ApoB100 in the control of intestinal lipid transport in response to dietary lipid intake, at least at low to moderate lipid levels.

Severe hypertriglyceridemia (HTG) due to chylomicronemia is associated with acute pancreatitis and is related to genetic disturbances in several proteins involved in triglyceride (TG) metabolism. Lipase maturation factor 1 (LMF1) is a protein essential for the maturation of lipoprotein lipase (LPL). In this study, we examined the genetic spectrum of the LMF1 gene among subjects with severe HTG and investigated the functional significance of 6 genetic variants in vitro. All 11 exons of the LMF1 gene were sequenced in 101 Thai subjects with severe HTG. For an in vitro study, we performed site-directed mutagenesis, transient expression in cld cells, and measured LPL protein and LPL activity. We identified 2 common variants [p.(Gly36Asp) and p.(Pro562Arg)] and 12 rare variants [p.(Thr143Met), p.(Asn249Ser), p.(Ala287Val), p.(Met346Val), p.(Thr395Ile), p.(Gly410Arg), p.(Asp433Asn), p.(Asp491Asn), p.(Asn501Tyr), p.(Ala504Val), p.(Arg523His), and p.(Leu563Arg)] in 29 patients. In vitro study of the p.(Gly36Asp), p.(Asn249Ser), p.(Ala287Val), p.(Asn501Tyr), p.(Pro562Arg) and p.(Leu563Arg) variants, however, revealed that both LPL mass and LPL activity in each of the transfected cells were not significantly different from those in the wild type LMF1 transfected cells, suggesting that these variants might not play a significant role in severe HTG phenotype in our subjects.

Elevations in plasma triglyceride are the result of overproduction and impaired clearance of triglyceride-rich lipoproteins—very low-density lipoproteins (VLDL) and chylomicrons. Hypertriglyceridemia is characterized by an accumulation in the circulation of large VLDL-VLDL1–and its lipolytic products, and throughout the VLDL-LDL delipidation cascade perturbations occur that give rise to increased concentrations of remnant lipoproteins and small, dense low-density lipoprotein (LDL). The elevated risk of atherosclerotic cardiovascular disease in hypertriglyceridemia is believed to result from the exposure of the artery wall to these aberrant lipoprotein species. Key regulators of the metabolism of triglyceride-rich lipoproteins have been identified and a number of these are targets for pharmacological intervention. However, a clear picture is yet to emerge as to how to relate triglyceride lowering to reduced risk of atherosclerosis.

Type 2 diabetes (T2D) is associated with increased risk of cardiovascular disease (CVD). In insulin resistant states such as the metabolic syndrome, overproduction and impaired clearance of liver-derived very-low-density lipoproteins and gut-derived chylomicrons (CMs) contribute to hypertriglyceridemia and elevated atherogenic remnant lipoproteins. Although ingested fat is the major stimulus of CM secretion, intestinal lipid handling and ultimately CM secretory rate is determined by numerous additional regulatory inputs including nutrients, hormones and neural signals that fine tune CM secretion during fasted and fed states. Insulin resistance and T2D represent perturbed metabolic states in which intestinal sensitivity to key regulatory hormones such as insulin, leptin and glucagon-like peptide-1 (GLP-1) may be altered, contributing to increased CM secretion. In this review, we describe the evidence from human and animal models demonstrating increased CM secretion in insulin resistance and T2D and discuss the molecular mechanisms underlying these effects. Several novel compounds are in various stages of preclinical and clinical investigation to modulate intestinal CM synthesis and secretion. Their efficacy, safety and therapeutic utility are discussed. Similarly, the effects of currently approved lipid modulating therapies such as statins, ezetimibe, fibrates, and PCSK9 inhibitors on intestinal CM production are discussed. The intricacies of intestinal CM production are an active area of research that may yield novel therapies to prevent atherosclerotic CVD in insulin resistance and T2D.

This review emphasizes the events that take place after the chylomicrons are secreted by the enterocytes through exocytosis. First, we will discuss the journey of how chylomicrons cross the basement membrane to enter the lamina propria. Then the chylomicrons have to travel across the lamina propria before they can enter the lacteals. To understand the factors affecting the trafficking of chylomicron particles across the lamina propria, it is important to understand the composition and properties of the lamina propria. With different degree of hydration, the pores of the lamina propria (sponge) changes. The greater the hydration, the greater the pore size and thus the easier the diffusion of the chylomicron particles across the lamina propria to enter the lacteals. The mechanism of the entry of lacteals is discussed in considerable details. We and others have demonstrated that intestinal fat absorption, but not the absorption of protein or carbohydrates, activates the intestinal mucosal mast cells to release many products including mucosal mast cell protease II in the rat. The activation of intestinal mucosal mast cells by fat absorption involves the process of chylomicron formation since the absorption of both medium and short-chain fatty acids do not activate the mast cells. Fat absorption has been associated with increased intestinal permeability. We hypothesize that there is a link between fat absorption, activation of mucosal mast cells, and the leaky gut phenomenon (increased intestinal permeability). Microbiome may also be involved in this chain of events associated with fat absorption. This review is presented in sequence under the following headings: (1) Introduction; (2) Structure and properties of the gut epithelial basement membrane; (3) Composition and physical properties of the interstitial matrix of the lamina propria; (4) The movement of chylomicrons across the interstitial matrix of the lamina propria and importance of the hydration of the interstitial matrix of the lamina propria and the movement of chylomicrons; (5) Entry of the chylomicrons into the intestinal lacteals; (6) Activation of mucosal mast cells by fat absorption and the metabolic consequences; and (7) Link between chylomicron transport, mucosal mast cell activation, leaky gut, and the microbiome.

Atherosclerosis is a multicausal disease characterized by the formation of cholesterol-containing plaque in the pronounced intima nearest to the heart’s elastic-type arteries that have high levels of blood circulation. Plaques are formed due to arterial pressure-induced damage to the endothelium in areas of turbulent blood flow. It is found in the majority of the Western population, including young people. This denies the monogenic mechanism of atherogenesis. In 1988, Orekhov et al. and Kawai et al. discovered that the presence of atherogenic (modified, including oxidized ones) LDLs is necessary for atherogenesis. On the basis of our discovery, suggesting that the overloading of enterocytes with lipids could lead to the formation of modified LDLs, we proposed a new hypothesis explaining the main factors of atherogenesis. Indeed, when endothelial cells are damaged and then pass through the G2 phase of their cell cycle they secrete proteins into their basement membrane. This leads to thickening of the basement membrane and increases its affinity to LDL especially for modified ones. When the enterocyte transcytosis pathway is overloaded with fat, very large chylomicrons are formed, which have few sialic acids, circulate in the blood for a long time, undergo oxidation, and can induce the production of autoantibodies. It is the sialic acids that shield the short forks of the polysaccharide chains to which autoantibodies are produced. Here, these data are evaluated from the point of view of our new model.

Men have a higher tendency to accumulate abdominal visceral fat compared to pre-menopausal women. The accumulation of abdominal visceral fat in men, which is a strong independent predictor of mortality, is mainly due to the higher dietary fat uptake by their abdominal visceral fat. Since dietary fat is absorbed by the enterocytes and transported to the circulation in the forms of chylomicrons and very low density lipoproteins (VLDLs), it is crucial to understand how these lipoproteins are different between men and women. The chylomicrons in men are generally bigger in size and more in quantity than those in women. During the postprandial state, these chylomicrons congest the lamina propria and the low-pressure lymphatics. In this paper, we propose that this congestion predisposes the chylomicron triglycerides to hydrolysis by lipoprotein lipase (LPL). The liberated fatty acids are then stored by the nearby abdominal visceral adipocytes, leading to the accumulation of abdominal visceral fat. These mechanisms perhaps explain why men, through their bigger and higher production of chylomicrons, are more likely to accumulate abdominal visceral fat than pre-menopausal women. This accumulation eventually leads to belly enlargement, which confers men their apple-shaped body.

Background/Aims: Non-alcoholic fatty liver disease (NAFLD) is an emerging metabolic disease. Although it leads to severe hepatic diseases including steatohepatitis, cirrhosis, and hepatic cancer, little is known about therapy to prevent and cure hepatic steatosis, the first step of NAFLD. We conducted this investigation to unveil the mechanism of hepatic steatosis. Methods: We established a novel chronic NAFLD mouse model through whole body irradiation and verified the model through histological and biochemical analysis. To find molecular mechanism for hepatic steatosis, we analyzed hepatic transcriptomic profiles in this model and selected target molecule. To induce the expression of lactotransferrin (Ltf) and regulate the NAFLD, growth hormone (GH) and coumestrol was introduced to hepatocyte and mice. The universal effect of coumestrol was confirmed by administration of coumestrol to NAFLD mouse model induced by high-fructose, high-fat, and MCD diet. Results: It was observed that decreased hepatic Ltf expression led to excessive hepatic lipid accumulation in NAFLD mouse. Furthermore, we found that GH was decreased in irradiated mice and functioned as an upstream regulator of Ltf expression. It was observed that GH could stimulate Ltf expression and prevent uptake of dietary lipids in hepatocytes, leading to rescue of NAFLD. Finally, we suggested that coumestrol, a kind of isoflavonoid, could be used as an inducer of hepatic Ltf expression through cooperation with the GH signaling pathway both in vitro and in vivo. Conclusions: Hepatic Ltf prevents hepatic steatosis through inhibition of dietary lipid uptake in radiation-induced NAFLD mouse model. We also suggest coumestrol as a drug candidate for prevention of NAFLD.

Purpose: The current study aims the lymphatic delivery of leflunomide loaded nanostructured lipid carriers (LNLC) for the treatment of rheumatoid arthritis, mainly focussed to enhance the lymphatic delivery via chylomicron formation, improved bioavailability and reduced systemic toxicity. Methods: Melt emulsification ultra-sonication method was used to formulate the nanostructured lipid carrier (NLC) containing leflunomide. Four batches were prepared by using various concentration of surfactants (tween 80 and poloxmer 188) and lipid mixtures (stearic acid and oleic acid). All the formulations were studied for various physiochemical properties Results: The formulation with increased concentration of lipid and surfactants showed highest entrapment efficiency (93.96 ± 0.47%) and better drug release (90.35%) at the end of 48 hrs. In vivo tests were carried out to determine the antiarthritic potential of the formulation in Sprague-dawley rats for a duration of 30d. The effect was evaluated by measuring the reduction in knee thickness. LNLC showed a marked reduction in inflammation compared to standard drug. Intestinal lymphatic uptake studies of LNLC were performed by intraduodenal administration and compared with leflunomide drug solution. The mesenteric lymph node was analysed by HPLC method and the concentration of drug was estimated. It showed that LNLC having highest uptake (40.34μg/ml) when compared with leflunomide drug solution (10.04μg/ml). Radiographic analysis and histopathological studies showed the formation of healthy cartilage after treatment period. Conclusion: The results suggested that LNLC has the potential to reduce the systemic toxicities associated with conventional therapy along with improved efficacy in the treatment of rheumatoid arthritis.

Fatty meals induce intestinal secretion of chylomicrons (CMs) containing apolipoprotein (Apo) B48. These CMs travel via the lymphatic system before entering the circulation. ApoB48 is produced after post-transcriptional RNA modification by Apobec-1 editing enzyme, exclusively in the small intestine of humans and most other mammals. In contrast, in the liver where Apobec-1 editing enzyme is not expressed (except in rats and mice), the unedited transcript encodes a larger protein, ApoB100, which is used in the formation of very low-density lipoproteins (VLDL) to transport liver-synthesized fat to peripheral tissues. Apobec-1 knockout (KO) mice lack the ability to perform ApoB RNA editing, and thus, express ApoB100 in the intestine. These mice, maintained on either a chow diet or high fat diet, have body weight gain and food intake comparable to their wildtype (WT) counterparts on the respective diet; however, they secrete larger triglyceride (TG)-rich lipoprotein particles and at a slower rate than the WT mice. Using a lymph fistula model, we demonstrated that Apobec-1 KO mice also produced fewer CMs and exhibited reduced lymphatic transport of TG in response to duodenal infusion of TG at a moderate dose; in contrast, the Apobec-1 KO and WT mice had similar lymphatic transport of TG when they received a high dose of TG. Thus, the smaller, energy-saving ApoB48 appears to play a superior role in comparison with ApoB100 in the control of intestinal lipid transport in response to dietary lipid intake, at least at low to moderate lipid levels. [ABSTRACT FROM AUTHOR]