Dietary Fat Absorption Research Articles

Lymphangiogenesis and Prostanoids as Regulators in Disease States

The lymphatic vessels have crucial roles in the regulation of interstitial fluids, immune surveillance and the absorption of dietary fat in the intestine. Lymphatic functions are also closely related to the pathogenesis of various disease states such as inflammatory responses, lymphedema, and metastasis of tumors. Lymphangiogenesis, the formation of new lymphatic vessels from pre-existing lymphatics is critical determinant of the above pathological conditions. Prostanoids including prostaglandins and thromboxanes are the metabolites of arachidonic acid, C-20 unsaturated fatty acid, and they exhibit a variety of actions via specific receptors. Although some kinds of growth factors are well-characterized in the lymphangiogenesis, there is accumulating evidence that prostaglandinsand thromboxanesare important regulators of lymphangiogenesis. Previously prostanoids are reported to have immediate actions on the smooth muscles and vasculatures, however, they work as inducers of growth factors or cytokines that regulate lymphangiogenesis, and modulate the prolymphangiogenic microenvironment. This review discusses our current understanding of prostanoids as regulators of lymphangiogenesis, and the emerging importance of the lymphangiogenesis as a therapeutic target.

Lipid-lowering effect of microencapsulated peptides from brewer's spent grain in high-sucrose diet-fed rats

Brewer's spent grain (BSG) -a byproduct generated from the processing of beer-brewing industry-is currently recognized as an important source of bioactive peptides with potential health benefits. In previous studies we demonstrated that peptides obtained from BSG (BSG-P) can exert in vitro biofunctional activities including hypolipidemic effects. However, there are no studies about the effects of gastrointestinal digestion on BSG lipid-lowering peptides and it is unknown whether the bioactive properties observed in vitro remain in vivo. The aims of this work were to evaluate the microencapsulation as strategy to preserve hypolipidemic BSG-P under a simulated gastrointestinal digestion, and the bioavailability of microencapsulated BSG-P using a rodent model of hyperlipidemia and other metabolic-related disorders induced by the consumption of a high-sucrose diet. In vitro studies showed that microencapsulation improved the BSG-P reduced hypolipidemic activity observed under a simulated gastrointestinal digestion by increasing the inhibition of the fat digestion enzymes, pancreatic lipase and cholesterol esterase. Furthermore, in vivo studies demonstrated that microencapsulated BSG-P were also able to reduce the increased serum lipid levels (triglycerides-TG- cholesterol and free fatty acids), energy intake, visceral adipocytes size and TG content observed in sucrose-rich diet-fed rats. This was accompanied by reduced liver lipids levels and the activities of key enzymes involved in dietary fat absorption. Therefore, our findings show that microencapsulation is a useful strategy to preserve the hypolipidemic activity of BSG-P and support the concept that microencapsulated BSG-P would be an interesting and cheaper natural source to prevent hyperlipidemias and its related-disorders.

Assessment of the association of the MOGAT1 and MOGAT3 gene with growth traits in different growth stages in Holstein calves.

The members of the monoacylglycerol acyltransferase (MOGAT) family are essential candidate genes that influence economic traits associated with triglyceride synthesis, dietary fat absorption, and storage in livestock. In addition, the MOGAT gene family may also play an essential function in human polygenic diseases, like type 2 diabetes and obesity. The present study was conducted on Holstein calves to find the association between MOGAT1, MOGAT3/g.A229G, and MOGAT3/g.G1627A and growth traits. The polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method was performed for genotyping the MOGAT1, MOGAT3/g.A229G, and MOGAT3/g.G1627A genes' locus using the TaqI, MspI, and BsuRI restriction enzyme. The allele frequency of A and G of the MOGAT1 locus was 0.79 and 0.21, respectively, while the genotype frequency was 0.65, 0.28, and 0.07 for AA, AG, and GG, respectively. While the allele and genotype frequencies of the MOGAT3/g.A229G locus were 00.57(), 0.43(), 0.35(), 0.45(), and 0.20(), the allele and genotype frequencies of the MOGAT3/g.G1627A locus were 0.49(), 0.51(), 0.25(), 0.49(), and 0.26(). Chi-square analysis showed that MOGAT3/g.G1627A distribution was at the Hardy–Weinberg disequilibrium ( 0.05), and MOGAT1 and MOGAT3/g.A229G distribution was at the Hardy–Weinberg equilibrium ( 0.05). In total, two statistical methods (general linear model (GLM) and PROC MIXED) were used to identify an association between gene locus and growth traits. An association analysis showed a statistically significant difference between the MOGAT1 and body weight, body length, and chest circumference, MOGAT3/g.A229G with average daily gain (ADG) and withers height, and MOGAT3/g.G1627A with body weight and body length ( 0.05). The results confirmed that the MOGAT1, MOGAT3/g.A229G, and MOGAT3/g.G1627A locus are strong candidate genes that could be considered molecular markers for growth traits in cattle breeding.

Pharmacotherapy in obesity: the current state and the near future

Background: In Korea, the prevalence of obesity, morbid obesity with serious complications, and childhood obesity are rapidly increasing. To control the obesity pandemic, both prevention and treatment are essential strategic targets. While lifestyle modification is fundamental in obesity treatment, due to the complex appetite-controlling system in the body and the rapidly Westernizing environment, more effective treatment tools are required.Current Concepts: There are 4 types of drugs that have been approved for the treatment of obesity in Korea. They are (1) appetite suppressants for short-term therapy, (2) dietary fat absorption inhibitors, (3) glucagon-like peptide-1 (GLP-1) receptor agonists, and (4) fixed-dose combination drugs for appetite control. However, a large amount of weight reduction cannot be achieved with these drugs. The greatest amount of weight reduction of approximately 11% has been reported for phentermine/topiramate combination treatment. Recently, peptide agents have been under development and 2 of these agents, semaglutide, a second generation GLP-1 receptor agonist, and tirzepatide, a glucose-dependent insulinotropic polypeptide/GLP-1 receptor dual agonist, are expected to be available in the near future.Discussion and Conclusion: Both semaglutide and tirzepatide are more effective than currently available anti-obesity drugs. Semaglutide and tirzepatide reduced the body weight of people with obesity without diabetes by 14.9% and 20.9%, respectively. However, because of the mechanism of GLP-1 receptor agonism, gastrointestinal adverse events, including nausea, diarrhea, vomiting, and abdominal pain, were problematic in many patients, although these adverse events were generally acceptable. Both drugs will be excellent options for obesity treatment in the near future.

Visual Identification of Trichosporon asahii, a Gut Yeast Associated with Obesity, Using an Enzymatic NIR Fluorescent Probe.

Lipase found in the gut microbiota participates in the digestion and absorption of dietary fats. As such, the gut microbiota is involved in the regulation of the host metabolism, affecting the levels of lipids and free fatty acids, ultimately resulting in obesity. In this study, an enzymatic activatable near-infrared fluorescent probe, DDAO-C6, was developed for visually sensing endogenous lipase from gut microbes. Using DDAO-C6, a cultivated intestinal yeast strain was rapidly identified from human feces that exhibited high lipase expression and was identified as Trichosporon asahii Y2. We then determined that the colonization of the gut of mice with T. asahii Y2 increased lipase activity in the digestive tract and promoted obesity and hyperlipidemia when the mice were fed high fat diets. Above all, the present research resulted in a fluorescence visualization tool for the functional investigation of gut microbiota associated with obesity and disorders of lipid metabolism.

Free Linoleic Acid and Oleic Acid Reduce Fat Digestion and Absorption In Vivo as Potent Pancreatic Lipase Inhibitors Derived from Sesame Meal

Pancreatic lipase catalyzes the cleavage of triacylglycerols at the oil–water interface, and is known as the dominant determiner of dietary fat digestion. Reducing dietary fat digestion and absorption by modulating the activity of pancreatic lipase has become a favorable strategy to tackle obesity. Orlistat is, at present, the only pancreatic lipase inhibitor approved for the treatment of obesity; however, an array of gastrointestinal adverse effects associated with orlistat limits its tolerability. As a safe alternative to orlistat, a number of natural product-derived compounds with varying degrees of pancreatic lipase inhibitory activity have been reported. We herein reported that bioactivity-guided fractionation of sesame meal led to the identification of free linoleic acid and oleic acid as potent inhibitors of porcine pancreatic lipase in vitro with an IC50 of 23.1 µg/mL (82.4 µM) and 11.7 µg/mL (41.4 µM), respectively. In rats, a single oral dose of the mixture of these fatty acids significantly suppressed the elevation of blood triacylglycerol level following fat intake. These results substantiate the role of free linoleic acid and oleic acid as a novel class of natural product-derived functional molecules that act as pancreatic lipase inhibitors, and their potential for healthy, routine-based weight management.

The Interaction between Intestinal ACSL5 Expression and Gut Microbiota in Mice Fed a High Fat Diet

ObjectivesA major contributor to the development of obesity is the excessive intake of calories and fat. Our preliminary data indicate that a critical step for the absorption of dietary fat is the acylation of FFA to acyl-CoA by enterocyte acyl-CoA long-chain synthetase 5 (ACSL5). In previous unpublished studies we demonstrated that mice with intestinal specific deficiency of ACSL5 (ACSL5int-/-) fed a high-fat diet (HFD) were protected against diet-induced obesity (DIO) secondary to reduced HFD intake. Since the composition of the intestinal microbiome has been demonstrated to modulate DIO and metabolism, the objective of this project is to explore the relative role of reduced HFD intake versus intestinal deficiency of ACSL5 on the composition of the host microbiome.MethodsThe intestinal deficiency of ACSL5 mouse model (ACSL5int-/-) and floxed littermates ACSL5loxP/loxP were fed either a low-fat diet (LFD, 4% fat) or a high-fat diet (HFD, 60% fat) for two weeks. Cecal contents were collected for 16S rDNA gene sequencing. For the pair-feeding study, one group of ACSL5int-/- mice and one group of ACSL5loxP/loxP mice received a HFD for 16 weeks ad libitum. At the same time, a second group of ACSL5loxP/loxP mice was pair-fed with the same amount of food ingested by ACSL5int-/- littermates.ResultsOur studies demonstrate that HFD fed ACSL5int-/- mice possess a significantly distinct microbiome structure compared to ACSL5loxP/loxP mice. Taxa analysis revealed that in 8 out of 11 ACSL5int-/- mice fed a HFD levels of Akkermansia muciniphila were present while it was not detected in any of the 8 ACSL5loxP/loxP mice. During pair-feeding, we observed that ACSL5int-/- mice consumed 20% less energy when fed a HFD and were protected against DIO and insulin resistance.ConclusionsReduced food intake resulting from intestine-specific deficiency of ACSL5 protects against the development of HFD-induced obesity and is associated with an altered microbial structure that is consistent with an improved metabolic profile. Ongoing studies using metagenomic sequencing will provide specific information on taxonomy at the species level, expression of genes and functional characterization of the microbiome of mice fed varying levels of high fat intake and intestinal ACSL5 deficiency.Funding SourcesUSDA/ARS-8050-51,000-097-02S, 5P30DK046200-29, 5R01DK119337-02, Atkins Foundation.

Bile acids directly bind and allosterically regulate the epithelial sodium channel

Bile acids are critical for the digestion and absorption of dietary fats and have important roles as signaling molecules. Bile acids are normally restricted to the enterohepatic circulation, but can be elevated in the blood and urine of patients with advanced liver diseases. The epithelial sodium channel (ENaC) mediates Na+ transport in the biliary epithelium, where it regulates bile viscosity, and in the aldosterone‐sensitive distal nephron, where it regulates extracellular fluid volume. We previously showed that bile acid regulation of ENaC depends on the position and stereochemistry of specific functional groups, but not on their chemico‐physical properties. To determine whether bile acids regulate ENaC in ex vivo native tissues, we performed patch clamp experiments on isolated split open renal tubules from mice, using recording pipettes backfilled with taurocholic acid (t‐CA) or taurohyodeoxycholic acid (t‐HDCA). Consistent with in vitro experiments, t‐CA increased ENaC open probability (PO) by 2‐fold while t‐HDCA decreased ENaC PO by nearly two‐thirds. To determine whether bile acids regulate ENaC through direct binding, we performed photoaffinity labeling experiments. We employed a bile acid derivative (p‐DCA) with diazirine and terminal alkyne groups that facilitate uv‐crosslinking and affinity purification, respectively. Using cultured Fisher Rat Thyroid cells transfected with ENaC, we found that the deoxycholic acid derivative (p‐DCA) crosslinked to the α, β, and γ subunits. To determine whether crosslinking was specific, we performed experiments in the presence of competing bile acids. Crosslinking to the β subunit was significantly reduced in the presence of deoxycholic acid (DCA). Crosslinking to the γ subunit was significantly reduced by taurocholic acid (t‐CA). These data suggest direct binding and multiple sites. To determine the effect of subunit composition on regulation, we measured the effect of t‐CA on Li+ currents in Xenopusoocytes expressing different functional ENaC subunit combinations. Channels composed of α subunits alone were strongly activated by t‐CA, followed by αβγ‐ and αβ‐ channels, suggesting that the α subunit is sufficient for ENaC sensitivity to t‐CA. Our data are consistent with bile acids directly binding all three ENaC subunits at multiple sites. Bile acid moieties provide for selective preferences for each of the sites, resulting in distinct effects for each bile acid.

Nutraceutical targeting of the bile acid receptor, farnesoid X receptor, for intestinal disease

IntroductionBile acids classically known for their roles in dietary fat absorption are now recognized as hormones critical to regulating intestinal and metabolic function, including mucosal immune responses, epithelial proliferation/apoptosis, and transepithelial transport and barrier function. Downregulation of the nuclear bile acid receptor, farnesoid X receptor (FXR), in intestinal epithelium occurs in inflammatory bowel disease and colorectal cancer, whereas FXR activation prevents disease progression in pre‐clinical models. Thus strategies to upregulate epithelial FXR expression have been proposed to treat such conditions. Previous studies suggest that some plant‐derived phytochemicals have the capacity to modulate FXR activity. Plant sources have been reported to contain such phytochemicals, which are proposed to modulate FXR.AimThe aim of the current study was to investigate the potential for developing plant extracts, rich in FXR‐modulating phytochemicals, as a novel nutraceutical‐based approach to treat and prevent intestinal diseases.MethodsT84 human colonic epithelial cells and primary cultures of murine colonic epithelial enteroids were employed to examine the effects of a common‐dietary phytochemical, denoted here as KFS1, and a KFS1‐rich plant extract on FXR expression and signaling in vitro. Ex vivo studies were carried out on human colonic tissue obtained during endoscopy with ethical approval from Beaumont Hospital. In vivo studies in C57BL/6 mice were carried out and proximal colonic tissue were examined with ethical approval from the HPRA. Expression of FXR and FGF19/15, an established marker of FXR activation, was assessed by qRT‐PCR, ELISA and immunoblotting. Data are expressed as mean ± SEM for a series of n experiments.ResultsKFS1 treatment (5 µM; 24hrs) increased FXR mRNA and protein expression in T84 cells by 4.2 ± 0.4 (p<0.05; n = 4) and 1.7 ± 0.1 fold (p<0.05; n = 7) respectively. KFS1 also enhanced FGF19 protein expression in response to the FXR agonist GW4064 (5 µM), by 4.1 ± 0.5 fold (p<0.001; n = 7). Similarly KFS1 upregulated FXR expression by 2.1 ± 0.4 fold in human biopsies (p<0.05; n = 6). Oral KFS1 administration to mice had a tendency to upregulate colonic epithelial FXR signaling in vivo and increased FXR expression and GW4064‐induced FGF15 by 2.3 ± 0.2 (p<0.01; n = 4) and 2.2 ± 0.1 fold (p<0.01; n = 4) in murine colonic enteroids. Finally a methanolic KFS1‐rich plant extract, denoted QE1, verified by LC/MS to contain KFS1, increased FXR protein expression in vitro by 1.8 ± 0.2 fold (p<0.05; n = 5) and enhanced GW4064‐induced FGF19 protein by 1.9 ± 0.1 fold (p<0.01; n = 9).ConclusionOur data demonstrate that KFS1‐containing plant extracts modulate expression and activity of FXR in the intestinal epithelium. Given the critical role of FXR in maintenance of gut health and metabolic function, such extracts have significant therapeutic and commercial potential to be developed as a novel first‐in‐class “FXR‐targeted nutraceutical” for treatment and prevention of common intestinal disorders.

GLP-2 Regulation of Dietary Fat Absorption and Intestinal Chylomicron Production via Neuronal Nitric Oxide Synthase (nNOS) Signaling.

Postprandial dyslipidemia is a metabolic condition commonly associated with insulin-resistant states, such as obesity and type 2 diabetes. It is characterized by the overproduction of intestinal chylomicron particles and excess atherogenic chylomicron remnants in circulation. We have previously shown that glucagon-like peptide 2 (GLP-2) augments dietary fat uptake and chylomicron production in insulin-resistant states; however, the underlying mechanisms remain unclear. Previous studies have implicated nitric oxide (NO) in the absorptive actions of GLP-2. In this study, we report a novel role for neuronal NO synthase (nNOS)-mediated NO generation in lipid uptake and chylomicron formation based on studies in C57BL/6J mice, nNOS-/- mice, and Syrian golden hamsters after intraduodenal and oral fat administration. GLP-2 treatment in wild-type (WT) mice significantly increased postprandial lipid accumulation and circulating apolipoprotein B48 protein levels, while these effects were abolished in nNOS-/- mice. nNOS inhibition in Syrian golden hamsters and protein kinase G (PKG) inhibition in WT mice also abrogated the effect of GLP-2 on postprandial lipid accumulation. These studies demonstrate a novel mechanism in which nNOS-generated NO is crucial for GLP-2-mediated lipid absorption and chylomicron production in both mouse and hamster models. Overall, our data implicate an nNOS-PKG-mediated pathway in GLP-2-mediated stimulation of dietary fat absorption and intestinal chylomicron production.

The meningeal lymphatic vasculature in neuroinflammation.

The lymphatic vasculature is a unidirectional network of lymphatic endothelial cells, whose main role is to maintain fluid homeostasis along with the absorption of dietary fat in the gastrointestinal organs and management and coordination of immune cell trafficking into lymph nodes during homeostasis and under inflammatory conditions. In homeostatic conditions, immune cells, such as dendritic cells, macrophages, or T cells can enter into the lymphatic vasculature and move easily through the lymph reaching secondary lymph nodes where immune cell activation or peripheral tolerance can be modulated. However, under inflammatory conditions such as pathogen infection, increased permeabilization of lymphatic vessels allows faster immune cell migration into inflamed tissues following a chemokine gradient, facilitating pathogen clearance and the resolution of inflammation. Interestingly, since the re-discovery of lymphatic vasculature in the central nervous system, known as the meningeal lymphatic vasculature, the role of these lymphatics as a key player in several neurological disorders has been described, with emphasis on the neurodegenerative process. Alternatively, less has been discussed about meningeal lymphatics and its role in neuroinflammation. In this review, we discuss current knowledge about the anatomy and function of the meningeal lymphatic vasculature and specifically analyze its contribution to different neuroinflammatory processes, highlighting the potential therapeutic target of meningeal lymphatic vasculature in these pathological conditions.

The monoacylglycerol acyltransferase pathway contributes to triacylglycerol synthesis in HepG2 cells

The monoacylglycerol acyltransferase (MGAT) pathway has a well-established role in the small intestine where it facilitates the absorption of dietary fat. In enterocytes, MGAT participates in the resynthesis of triacylglycerol using substrates (monoacylglycerol and fatty acids) generated in the gut lumen from the breakdown of triacylglycerol consumed in the diet. MGAT activity is also present in the liver, but its role in triacylglycerol metabolism in this tissue remains unclear. The predominant MGAT isoforms present in human liver appear to be MGAT2 and MGAT3. The objective of this study was to use selective small molecule inhibitors of MGAT2 and MGAT3 to determine the contributions of these enzymes to triacylglycerol production in liver cells. We found that pharmacological inhibition of either enzyme had no effect on TG mass in HepG2 cells but did alter lipid droplet size and number. Inhibition of MGAT2 did result in decreased DG and TG synthesis and TG secretion. Interestingly, MGAT2 preferentially utilized 2-monoacylglycerol derived from free glycerol and not from exogenously added 2-monoacylglycerol. In contrast, inhibition of MGAT3 had very little effect on TG metabolism in HepG2 cells. Additionally, we demonstrated that the MGAT activity of DGAT1 only makes a minor contribution to TG synthesis in intact HepG2 cells. Our data demonstrated that the MGAT pathway has a role in hepatic lipid metabolism with MGAT2, more so than MGAT3, contributing to TG synthesis and secretion.

Bile Acids Gate Dopamine Transporter Mediated Currents.

Bile acids (BAs) are molecules derived from cholesterol that are involved in dietary fat absorption. New evidence supports an additional role for BAs as regulators of brain function. Sterols such as cholesterol interact with monoamine transporters, including the dopamine (DA) transporter (DAT) which plays a key role in DA neurotransmission and reward. This study explores the interactions of the BA, obeticholic acid (OCA), with DAT and characterizes the regulation of DAT activity via both electrophysiology and molecular modeling. We expressed murine DAT (mDAT) in Xenopus laevis oocytes and confirmed its functionality. Next, we showed that OCA promotes a DAT-mediated inward current that is Na+-dependent and not regulated by intracellular calcium. The current induced by OCA was transient in nature, returning to baseline in the continued presence of the BA. OCA also transiently blocked the DAT-mediated Li+-leak current, a feature that parallels DA action and indicates direct binding to the transporter in the absence of Na+. Interestingly, OCA did not alter DA affinity nor the ability of DA to promote a DAT-mediated inward current, suggesting that the interaction of OCA with the transporter is non-competitive, regarding DA. Docking simulations performed for investigating the molecular mechanism of OCA action on DAT activity revealed two potential binding sites. First, in the absence of DA, OCA binds DAT through interactions with D421, a residue normally involved in coordinating the binding of the Na+ ion to the Na2 binding site (Borre et al., J. Biol. Chem., 2014, 289, 25764–25773; Cheng and Bahar, Structure, 2015, 23, 2171–2181). Furthermore, we uncover a separate binding site for OCA on DAT, of equal potential functional impact, that is coordinated by the DAT residues R445 and D436. Binding to that site may stabilize the inward-facing (IF) open state by preventing the re-formation of the IF-gating salt bridges, R60-D436 and R445-E428, that are required for DA transport. This study suggests that BAs may represent novel pharmacological tools to regulate DAT function, and possibly, associated behaviors.

Molecular Regulation of Bile Acid Homeostasis.

Bile acids have been known for decades to aid in the digestion and absorption of dietary fats and fat-soluble vitamins in the intestine. The development of gene knockout mice models and transgenic humanized mouse models have helped us understand other functions of bile acids, such as their role in modulating fat, glucose, and energy metabolism, and in the molecular regulation of the synthesis, transport, and homeostasis of bile acids. The G-protein coupled receptor TGR5 regulates the bile acid induced alterations of intermediary metabolism, whereas the nuclear receptor FXR regulates bile acid synthesis and homeostasis. However, this review indicates that unidentified factors in addition to FXR must exist to aid in the regulation of bile acid synthesis and homeostasis. SIGNIFICANCE STATEMENT: This review captures the present understanding of bile acid synthesis, the role of bile acid transporters in the enterohepatic circulation of bile acids, the role of the nuclear receptor FXR on the regulation of bile acid synthesis and bile acid transporters, and the importance of bile acids in activating GPCR signaling via TGR5 to modify intermediary metabolism. This information is useful for developing drugs for the treatment of various hepatic and intestinal diseases, as well as the metabolic syndrome.

202: Additional dietary fat absorption characteristics of the lysophosphatidylcholine rich nutritional product in people with CF and PI

202: Additional dietary fat absorption characteristics of the lysophosphatidylcholine rich nutritional product in people with CF and PI

Deficiency of intestinal Bmal1 prevents obesity induced by high-fat feeding

The role of intestine clock in energy homeostasis remains elusive. Here we show that mice with Bmal1 specifically deleted in the intestine (Bmal1iKO mice) have a normal phenotype on a chow diet. However, on a high-fat diet (HFD), Bmal1iKO mice are protected against development of obesity and related abnormalities such as hyperlipidemia and fatty livers. These metabolic phenotypes are attributed to impaired lipid resynthesis in the intestine and reduced fat secretion. Consistently, wild-type mice fed a HFD during nighttime (with a lower BMAL1 expression) show alleviated obesity compared to mice fed ad libitum. Mechanistic studies uncover that BMAL1 transactivates the Dgat2 gene (encoding the triacylglycerol synthesis enzyme DGAT2) via direct binding to an E-box in the promoter, thereby promoting dietary fat absorption. Supporting these findings, intestinal deficiency of Rev-erbα, a known BMAL1 repressor, enhances dietary fat absorption and exacerbates HFD-induced obesity and comorbidities. Moreover, small-molecule targeting of REV-ERBα/BMAL1 by SR9009 ameliorates HFD-induced obesity in mice. Altogether, intestine clock functions as an accelerator in dietary fat absorption and targeting intestinal BMAL1 may be a promising approach for management of metabolic diseases induced by excess fat intake.

Susceptible genetic polymorphisms and their association with adverse effects of orlistat therapy

Orlistat is a tetrahydrolipstatin, which inhibits both pancreatic and gastric lipase enzymes in the gut and prevents the absorption of dietary fats in the intestine. Therefore, it is widely used as an anti-obesity medication to control and manage body weight in obese patients worldwide. Despite this, the mounting number of clinical studies report that orlistat treatment induces adverse effects like pancreatitis, hepatic failure, kidney stone, acute oxalate nephropathy, and others. Although various factors could mediate the adverse effects of orlistat, emerging shreds of evidence suggest that genetic polymorphism-associated factors could be the primary reason for the cause. Hence, in this review, we first collated the most critical clinical adverse effects caused by orlistat and then appraised the susceptible genetic polymorphism that could further worsen the adverse effects of orlistat. Nonetheless, this review warrants similar conceptual approaches to understand orlistat's adverse effects in the selective genetic polymorphism and improve the therapeutic outcome of orlistat. • Orlistat is an anti-obesity medication widely used in the control and management of weight in obese patients worldwide. • The orlistat acts by inhibiting the lipase enzymes and prevent the breakdown of TG in the intestine. • Orlistat therapy has been cautioned with clinical adverse effects. • The possible association of genetic polymorphism and adverse effects of orlistat remains elusive. • Our analysis collated the selective clinically reported genes susceptible to the critical adverse effects of orlistat.

The Roles of Cytoplasmic Lipid Droplets in Modulating Intestinal Uptake of Dietary Fat.

Dietary fat absorption is required for health but also contributes to hyperlipidemia and metabolic disease when dysregulated. One step in the process of dietary fat absorption is the formation of cytoplasmic lipid droplets (CLDs) in small intestinal enterocytes; these CLDs serve as dynamic triacylglycerol storage organelles that influence the rate at which dietary fat is absorbed. Recent studies have uncovered novel factors regulating enterocyte CLD metabolism that in turn influence the absorption of dietary fat. These include peroxisome proliferator-activated receptor α activation, compartmentalization of different lipid pools, the gut microbiome, liver X receptor and farnesoid X receptor activation, obesity, and physiological factors stimulating CLD mobilization. Understanding how enterocyte CLD metabolism is regulated is key in modulating the absorption of dietary fat in the prevention of hyperlipidemia and its associated metabolic disorders.

Structure and Function of Pancreatic Lipase-Related Protein 2 and Its Relationship With Pathological States.

Pancreatic lipase is critical for the digestion and absorption of dietary fats. The most abundant lipolytic enzymes secreted by the pancreas are pancreatic triglyceride lipase (PTL or PNLIP) and its family members, pancreatic lipase-related protein 1 (PNLIPRP1or PLRP1) and pancreatic lipase-related protein 2 (PNLIPRP2 or PLRP2). Unlike the family’s other members, PNLIPRP2 plays an elemental role in lipid digestion, especially for newborns. Therefore, if genetic factors cause gene mutation, or other factors lead to non-expression, it may have an effect on fat digestion and absorption, on the susceptibility to pancreas and intestinal pathogens. In this review, we will summarize what is known about the structure and function of PNLIPRP2 and the levels of PNLIPRP2 and associated various pathological states.

Supplementation of Bile Acids and Lipase in Broiler Diets for Better Nutrient Utilization and Performance: Potential Effects and Future Implications – A Review

Abstract Bile acids are used for better emulsification, digestion and absorption of dietary fat in chicken, especially in early life. Similarly, exogenous lipases have also been used for the improvement of physiological limitation of the chicken digestive system. Owing to potential of both bile acids and lipases, their use has been increased in recent years, for better emulsification of dietary fat and improvement of growth performance in broilers. In the past, pancreatic lipases were used for supplementation, but recently, microbial lipase is getting attention in poultry industry as a hydrolysis catalyst. Bile acids strengthen the defence mechanism of body against bacterial endotoxins and also play a key role in lipid regulation and sugar metabolism as signaling molecules. It has been demonstrated that bile acids and lipases may improve feed efficiency by enhancing digestive enzyme activity and ultimately leading to better fat digestion and absorption. Wide supplemental range of bile acids (0.004% to 0.25%) and lipases (0.01% to 0.1%) has been used in broiler diets for improvement of fat digestibility and their performance. Combinations of different bile acids have shown more potential to improve feed efficiency (by 7.14%) even at low (0.008%) levels as compared to any individual bile acid. Lipases at a lower level of 0.03% have exhibited more promising potential to improve fat digestibility and feed efficiency. However, contradicting results have been published in literature, which needs further investigations to elucidate various nutritional aspects of bile acids and lipase supplementation in broiler diet. This review focuses on providing insight on the mechanism of action and potential application of bile acids and lipases in broiler diets. Moreover, future implications of these additives in poultry nutrition for enhancing nutrient utilization and absorption are also discussed.