Enterocytes rely on purine biosynthesis/slavage pathway to facilitate dietary fat absorption-lipidomics
Ontology highlight
ABSTRACT:
INSTRUMENT(S): LC-QE Orbitrap/MS
ORGANISM(S): Mouse Intestine
SUBMITTER: 
Jiangjiang Zhu
PROVIDER: MSV000100414 | MassIVE | Thu Jan 08 08:59:00 GMT 2026
REPOSITORIES: MassIVE
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Project description:Triacylglyceride (TAG) synthesis in the small intestine determines the absorption of dietary fat, but the mechanisms underlying are largely unknown. Here, we report that the RNA-binding protein HuR (ELAVL1) promotes TAG synthesis in the small intestine. HuR associates with the 3’UTR of Dgat2 mRNA and the introns 1 of Mgat2 pre-mRNA. Association of HuR with Dgat2 3’UTR stabilizes Dgat2 mRNA, while association of HuR with intron 1 of Mgat2 pre-mRNA promotes the processing of Mgat2 pre-mRNA. Intestinal epithelium-specific HuR knockout reduces the expression of DGAT2 and MGAT2, thereby reducing the dietary fat absorption through TAG synthesis and mitigating high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and obesity. Our findings highlight a critical role of HuR in promoting dietary fat absorption.
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Project description:Triacylglyceride (TAG) synthesis in the small intestine determines the absorption of dietary fat, but the mechanisms underlying are largely unknown. Here, we report that the RNA-binding protein HuR (ELAVL1) promotes TAG synthesis in the small intestine. HuR associates with the 3’UTR of Dgat2 mRNA and the introns 1 of Mgat2 pre-mRNA. Association of HuR with Dgat2 3’UTR stabilizes Dgat2 mRNA, while association of HuR with intron 1 of Mgat2 pre-mRNA promotes the processing of Mgat2 pre-mRNA. Intestinal epithelium-specific HuR knockout reduces the expression of DGAT2 and MGAT2, thereby reducing the dietary fat absorption through TAG synthesis and mitigating high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and obesity. Our findings highlight a critical role of HuR in promoting dietary fat absorption.
2024-01-10 | GSE252591 | GEO
Project description:Helicobacter pylori is a chronic colonizer of the gastric epithelium and plays a major role in the development of gastritis, peptic ulcer disease, and gastric cancer. In its coevolution with humans, the streamlining of the H. pylori genome has resulted in a significant reduction in metabolic pathways, one being purine nucleotide biosynthesis. Bioinformatic analysis has revealed that H. pylori lacks the enzymatic machinery for de novo production of IMP, the first purine nucleotide formed during GTP and ATP biosynthesis. This suggests that H. pylori must rely heavily on salvage of purines from the environment. In this study, we deleted several genes putatively involved in purine salvage and processing. The growth and survival of these mutants were analyzed in both nutrient-rich and minimal media, and the results confirmed the presence of a robust purine salvage pathway in H. pylori. Of the two phosphoribosyltransferase genes found in the H. pylori genome, only gpt appears to be essential, and an Δapt mutant strain was still capable of growth on adenine, suggesting that adenine processing via Apt is not essential. Deletion of the putative nucleoside phosphorylase gene deoD resulted in an inability of H. pylori to grow on purine nucleosides or the purine base adenine. Our results suggest a purine requirement for growth of H. pylori in standard media, indicating that H. pylori possesses the ability to utilize purines and nucleosides from the environment in the absence of a de novo purine nucleotide biosynthesis pathway.
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Project description:ObjectivesExisting reference ranges for stool fat and energy absorption were developed using subjects in controlled environments on precise diets. This study measured energy and fat absorption in healthy, community-dwelling adults eating a moderate-to-high fat American diet via stool- and serum-based methods.MethodsThis was a secondary analysis of healthy subjects recruited as the comparison group in a chronic pancreatitis study. Subjects recorded dietary intake and collected stool over 3-day periods. Stool was analyzed for fat content using the coefficient of fat absorption and for energy content using bomb calorimetry. The malabsorption blood test (MBT) was used to measure dietary fat absorption.ResultsNineteen subjects had mean daily stool measures of 143 g wet weight, 4.1 g of fat, and 178 kcal. The mean coefficients of fat and energy absorption were 96% and 93%, respectively. The mean MBT area under the curve cut-point was greater than 8 mg·h/dL.ConclusionsThis study confirms the historical reference range for the coefficient of fat absorption in contemporary healthy, community-dwelling adults on a moderate-to-high fat diet. The study contributes to the development of reference range values for multiple bomb calorimetry-based outcomes of stool energy losses and to the serum-based MBT as a promising method for measuring fat absorption.
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Project description:Enterocytes, the absorptive cells of the small intestine, mediate the process of dietary fat absorption by secreting triacylglycerol (TAG) into circulation. When levels of dietary fat are high, TAG is stored in cytoplasmic lipid droplets (CLDs) and sequentially hydrolyzed for ultimate secretion. Mice with deficiency in acyl CoA: diacylglycerol acyltransferase 1 (Dgat1-/- mice) were previously reported to have a reduced rate of intestinal TAG secretion and abnormal TAG accumulation in enterocyte CLDs. This unique intestinal phenotype is critical to their resistance to diet-induced obesity; however, the underlying mechanism remains unclear. Emerging evidence shows that lysosomal TAG hydrolysis contributes to autophagy-mediated CLD mobilization termed lipophagy, and when disrupted results in CLD accumulation. In order to study how lipophagy contributes to the unique intestinal phenotype of Dgat1-/- mice, enterocytes from wild-type (WT) and Dgat1-/- mice were examined at 2 and 6 h after oral oil gavage. Through ultrastructural analysis we observed TAG present within autophagic vesicles (AVs) in mouse enterocytes, suggesting the role of lipophagy in intestinal CLD mobilization during dietary fat absorption. Furthermore, we found that Dgat1-/- mice had abnormal TAG accumulation within AVs and less acidic lysosomes compared to WT mice. Together these findings suggest that the delayed dietary fat absorption seen in Dgat1-/- mice is, in part, due to the dysregulated flux of autophagy-mediated CLD mobilization and impairment of lysosomal acidification in enterocytes. The present study highlights the critical role of lysosome in enterocyte CLD mobilization for proper dietary fat absorption.
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Project description:BackgroundIn blood and tissues, dietary and endogenously generated fatty acids (FAs) occur in free form or as part of complex lipid molecules that collectively represent the lipidome of the respective tissue. We assessed associations of plasma lipids derived from high-resolution lipidomics with incident cardiometabolic diseases and subsequently tested if the identified risk-associated lipids were sensitive to dietary fat modification.MethodsThe EPIC Potsdam cohort study (European Prospective Investigation into Cancer and Nutrition) comprises 27 548 participants recruited within an age range of 35 to 65 years from the general population around Potsdam, Germany. We generated 2 disease-specific case cohorts on the basis of a fixed random subsample (n=1262) and all respective cohort-wide identified incident primary cardiovascular disease (composite of fatal and nonfatal myocardial infarction and stroke; n=551) and type 2 diabetes (n=775) cases. We estimated the associations of baseline plasma concentrations of 282 class-specific FA abundances (calculated from 940 distinct molecular species across 15 lipid classes) with the outcomes in multivariable-adjusted Cox models. We tested the effect of an isoenergetic dietary fat modification on risk-associated lipids in the DIVAS randomized controlled trial (Dietary Intervention and Vascular Function; n=113). Participants consumed either a diet rich in saturated FAs (control), monounsaturated FAs, or a mixture of monounsaturated and n-6 polyunsaturated FAs for 16 weeks.ResultsSixty-nine lipids associated (false discovery rate<0.05) with at least 1 outcome (both, 8; only cardiovascular disease, 49; only type 2 diabetes, 12). In brief, several monoacylglycerols and FA16:0 and FA18:0 in diacylglycerols were associated with both outcomes; cholesteryl esters, free fatty acids, and sphingolipids were largely cardiovascular disease specific; and several (glycero)phospholipids were type 2 diabetes specific. In addition, 19 risk-associated lipids were affected (false discovery rate<0.05) by the diets rich in unsaturated dietary FAs compared with the saturated fat diet (17 in a direction consistent with a potential beneficial effect on long-term cardiometabolic risk). For example, the monounsaturated FA-rich diet decreased diacylglycerol(FA16:0) by 0.4 (95% CI, 0.5-0.3) SD units and increased triacylglycerol(FA22:1) by 0.5 (95% CI, 0.4-0.7) SD units.ConclusionsWe identified several lipids associated with cardiometabolic disease risk. A subset was beneficially altered by a dietary fat intervention that supports the substitution of dietary saturated FAs with unsaturated FAs as a potential tool for primary disease prevention.
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Project description:ObjectiveExposure to 60% high fat diet (HFD) leads to a robust consummatory preference over well-balanced chow standard diet (SD) when mice are presented with a choice. This passive HFD-induced SD devaluation following HFD challenge and withdrawal is highlighted by the significant reduction in SD food intake even in states of caloric deprivation. The elements of HFD that lead to this SD depreciation remains unclear. Possibly important factors include the amount and type of fat contained in a diet as well as past eating experiences dependent on sensory properties including taste and post ingestive feedback. We aimed to explore the role of these components to HFD-induced SD devaluation.MethodsWildtype mice were longitudinally presented discrete HFDs in conjunction with SD and feeding and metabolic parameters were analyzed. A separate cohort of animals were assessed for acute HFD preference in 3 conditions: 1) ad libitum fed (sated), 2) overnight fasted (physiologically hungry), and 3) ad libitum fed (artificially hungry), elicited through chemogenetic Agouti-related peptide (AgRP) neuron activation. Population dynamics of AgRP neurons were recorded to distinct inaccessible and accessible diets both before and after consummatory experience. Transient receptor potential channel type M5 (TRPM5) knockout mice were used to investigate the role of fat taste perception and preference to HFD-induced SD devaluation. The clinically approved lipase inhibitor orlistat was used to test the contribution of fat absorption to HFD-induced SD devaluation.ResultsHFD-induced SD devaluation is dependent on fat content, composition, and preference. This effect scaled both in strength and latency with higher percentages of animal fat. 60% HFD was preferred and almost exclusively consumed in preference to other diets across hours and days, but this was not as evident upon initial introduction over seconds and minutes, suggesting ingestive experience is critical. Optical fiber photometry recordings of AgRP activity supported this notion as neuronal suppression by the different diets was contingent on prior intake. While taste transduced via TRPM5 influenced HFD-evoked weight gain, it failed to impact either HFD preference or HFD-induced SD devaluation. Perturbation of post ingestive feedback through orlistat-mediated diminishment of fat absorption prevented HFD-evoked weight gain and abolished HFD-induced SD devaluation.ConclusionsPost ingestive feedback via fat digestion is vital for expression of HFD-induced SD devaluation.
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