UNASSIGNED: There are no studies investigating the direct effects of elevated xanthine oxidase (XO) on lipid metabolism disorders. Here, we aimed to clarify the role of XO in lipid metabolism in a prospective cohort study and elucidate the underlying mechanisms.
UNASSIGNED: The association between serum XO activity and metabolic associated steatotic liver disease (MASLD) was examined in Cox proportional hazard models in a population-based cohort of 3,358 participants (20-75 years) at baseline. In addition, mouse models were used to investigate the underlying mechanism for the association between overexpression of XO and the lipid metabolism disorders.
UNASSIGNED: After an average 5.8 years of follow up, we found elevated serum XO activity was associated with an increased risk of developing MASLD (hazard ratio [HR]: 2.08; 95% CI: 1.44-3.01; p-trend <0.001). Moreover, serum XO activity was significantly associated with serum triglyceride levels (r = 0.68, p <0.001). We demonstrated that hepatic XO expression increased in liver samples from patients with MASLD. Using tissue-specific Xdh knockin mice, we observed rapid lipid metabolism disorders under a high-fat diet rather than a normal chow diet. We found that XO overexpression promotes the absorption of excess dietary fat in the small intestine. Inhibition of XO also significantly reduced the absorption of fat in mice fed a high-fat diet.
UNASSIGNED: Our study clarified the association between serum XO activity levels and the development of MASLD in a large population-based prospective cohort study. Furthermore, our mouse models demonstrated that XO overexpression promotes lipid accumulation through mechanisms involving excessive fat absorption by the small intestine.
UNASSIGNED: Using a prospective population-based cohort and various animal models, we have identified novel mechanisms by which xanthine oxidase regulates lipid metabolism. Our findings indicate that xanthine oxidase overexpression promotes lipid accumulation by increasing the absorption of excess dietary fat and possibly facilitating lipid transport in vivo. These results could be important for the development of therapies to treat diseases associated with lipid metabolism disorders.

UNASSIGNED: Endothelial cells have a crucial function in transporting and exchanging various nutrients. O-GlcNAcylation, mediated by O-GlcNAc transferase (OGT), involves the addition of N-acetylglucosamine to proteins and serves as an intracellular nutrient sensing mechanism. However, the role of O-GlcNAcylation in endothelial cells remains poorly understood.
UNASSIGNED: This study investigated the role of O-GlcNAcylation in endothelial cells.
UNASSIGNED: Endothelial-cell-specific Ogt -knockout mice (Ogt-ECKO) were generated by crossing Ogt-floxed mice (Ogt-flox) with VE-Cadherin Cre ERT2 mice. Ogt-ECKO mice and Ogt-flox control mice were subjected to a normal or high-fat diet, and their body weight, glucose metabolism, and lipid metabolism were examined.
UNASSIGNED: Ogt-ECKO mice exhibited reduced body weight compared with Ogt-flox control mice under a high-fat diet. Lipid absorption was significantly impaired in Ogt-ECKO mice. Changes in the intercellular junctions of small intestinal lacteal endothelial cells from a button-like to a zipper-like configuration were observed. Furthermore, Ogt-ECKO mice showed decreased expression of VEGFR3. The administration of a nitric oxide donor restored lipid absorption and reversed the morphological alterations in Ogt-ECKO mice.
UNASSIGNED: These findings demonstrate the critical role of O-GlcNAcylation in endothelial cells in lipid absorption in the intestine through the modulation of lacteal junction morphology. These results provide novel insight into the metabolic regulatory mechanisms under physiological conditions and have implications for the development of new therapeutic strategies for obesity.

BACKGROUND: Coffee leaves are a major source of bioactive components and are used as ethnomedicine. However, despite their traditional medicinal use, information about their effects on antihyperlipidemia remains limited.
METHODS: The aims of this study were to evaluate the main components of leaf extracts from Arabica and Robusta coffees and to examine the potential of these coffee leaves in reducing lipid digestion and absorption in vitro.
RESULTS: Coffee leaf extracts from Arabica coffee contain a high amount of caffeine, whereas extracts from Robusta coffee contain high amounts of chlorogenic acid (CGA) and caffeine. Additionally, leaf extracts from Arabica and Robusta coffee demonstrated the inhibition of pancreatic lipase, decreased micellar cholesterol solubility, and reduced bile acid binding. Furthermore, these extracts resulted in a reduction in cholesterol uptake in Caco-2 cells. Molecular docking experiments supported this discovery, showing CGA and caffeine binding to Niemann-Pick C1-like 1 (NPC1L1), a key protein in cholesterol absorption. The results indicated that CGA and caffeine can competitively bind to NPC1L1 at the cholesterol binding pocket, reducing its cholesterol binding rate. These findings suggest that coffee leaves might help suppress lipid absorption and digestion, highlighting their potential use in preventing and treating hyperlipidemia.

UNASSIGNED: Platycodin D (PD) has been reported to treat metabolic diseases, including non-alcoholic fatty liver disease. In addition, platycodin D has been reported to activate intestinal 5\'AMP-activated protein kinase (AMPK) phosphorylation levels, thereby reducing lipid absorption. Therefore, the aim of this study is to explore whether PD activation of intestinal AMPK and reduced lipid absorption can improve non-alcoholic fatty liver disease.
UNASSIGNED: Clean-grade male C57/BL mice were fed a high-fat diet (HFD) (containing 60% calories) for 16 weeks, and oral PD (10 mg/kg/day) was administered at the same time. The liver and intestines were the collected, and the intestines were tested. The expressions of lipid absorption genes (CD36, NPC1L1, and ApoB), the serum total triglyceride (TG) and total cholesterol (TC) levels in the intestines and livers, the fecal free fatty acid (FFA) levels, and the expression of AMPK phosphorylated proteins in the intestines were examined using Western blot analyses. The lipid distribution in the livers, intestines, and fat was detected using Oil Red O and hematoxylin and eosin (H&E) staining. A colon cancer cell line (Caco2) was used to confirm the effect of PD on the cellular lipid uptake in vitro. In addition, serum inflammatory factors and liver enzymes were measured to clarify the impact of PD on the circulation of metabolic syndrome. Leptin-deficient mice (OB) were then used to further explore the improvement of PD on body weight and blood lipids.
UNASSIGNED: PD had a very significant therapeutic or preventive effect on metabolic syndrome and fatty liver induced by a high-fat diet. PD improved body weight, insulin sensitivity, and glucose tolerance in mice fed a high-fat diet and also prevented non-alcoholic fatty liver disease, reduced blood lipid levels, and increased fecal lipid excretion. In addition, PD reduced lipid absorption by activating the intestinal AMPK protein, which may have involved the inhibition of the gene expression levels of intestinal lipid absorption genes (CD36, NPC1L1, and ApoB). The combined effect of these factors improved hepatic lipid accumulation and lipid accumulation in adipose tissue. It was further found that PD also improved the body weights and blood lipid levels of leptin-deficient mice (OB) mice.
UNASSIGNED: PD had a very strong therapeutic effect on mice under a high-fat diet. PD reduced high-fat diet-induced obesity and non-alcoholic fatty liver disease by inhibiting intestinal fat absorption.

Numerous studies have reported critical roles for the gut microbiota in obesity. However, the specific microbes that causally contribute to obesity and the underlying mechanisms remain undetermined. Here, we conducted shotgun metagenomic sequencing in a Chinese cohort of 631 obese subjects and 374 normal-weight controls and identified a Megamonas-dominated, enterotype-like cluster enriched in obese subjects. Among this cohort, the presence of Megamonas and polygenic risk exhibited an additive impact on obesity. Megamonas rupellensis possessed genes for myo-inositol degradation, as demonstrated in vitro and in vivo, and the addition of myo-inositol effectively inhibited fatty acid absorption in intestinal organoids. Furthermore, mice colonized with M. rupellensis or E. coli heterologously expressing the myo-inositol-degrading iolG gene exhibited enhanced intestinal lipid absorption, thereby leading to obesity. Altogether, our findings uncover roles for M. rupellensis as a myo-inositol degrader that enhances lipid absorption and obesity, suggesting potential strategies for future obesity management.

Colchicine (COL) is known for its ability to inhibit the formation of intestinal chylomicrons and has been utilized as a non-surgical tool to explore drug absorption via the intestinal lymphatics. However, there is limited understanding of its pharmacokinetics and its relationship to effect and toxicity with the doses used. This study aimed to provide comprehensive COL pharmacokinetic data and correlate it with the lymphatic-blocking and toxicological effects of low-doses. Male Sprague-Dawley rats with jugular-vein cannulation (JVC) received 0.1 to 0.5 mg/kg COL via oral, 0.25 mg/kg intraperitoneal, and 0.1 mg/kg intravenous routes, followed by blood and urine sampling for LC-MS/MS analysis. Effects on lipid absorption were assessed in another eight JVC rats receiving peanut oil with and without COL, followed by blood pharmacokinetic and plasma biochemistry analysis. The results revealed that COL exhibited moderate extraction ratio and high volume of distribution, with low oral bioavailability (<8%). About 20 % was recovered in the urine after parenteral dosing. Modest but significant reductions in cholesterol absorption was observed after oral doses of 0.5 mg/kg, accompanied by signs of inflammation and increased liver enzymes persisting for a week. The effect of COL on triglycerides formation was not significant. Despite its use as a non-surgical tool in rats to investigate drug absorption via the lymphatic pathway, COL demonstrated increased levels of liver function enzymes, emphasizing the need for caution and dose optimization in its utilization.

Unhealthy lifestyles (high-fat diet, smoking, alcohol consumption, too little exercise, etc.) in the current society are prone to cause lipid metabolism disorders affecting the health of the organism and inducing the occurrence of diseases. Saponins, as biologically active substances present in plants, have lipid-lowering, inflammation-reducing, and anti-atherosclerotic effects. Saponins are thought to be involved in the regulation of lipid metabolism in the body; it suppresses the appetite and, thus, reduces energy intake by modulating pro-opiomelanocortin/Cocaine amphetamine regulated transcript (POMC/CART) neurons and neuropeptide Y/agouti-related peptide (NPY/AGRP) neurons in the hypothalamus, the appetite control center. Saponins directly activate the AMP-activated protein kinase (AMPK) signaling pathway and related transcriptional regulators such as peroxisome-proliferator-activated-receptors (PPAR), CCAAT/enhancer-binding proteins (C/EBP), and sterol-regulatory element binding proteins (SREBP) increase fatty acid oxidation and inhibit lipid synthesis. It also modulates gut-liver interactions to improve lipid metabolism by regulating gut microbes and their metabolites and derivatives-short-chain fatty acids (SCFAs), bile acids (BAs), trimethylamine (TMA), lipopolysaccharide (LPS), et al. This paper reviews the positive effects of different saponins on lipid metabolism disorders, suggesting that the gut-liver axis plays a crucial role in improving lipid metabolism processes and may be used as a therapeutic target to provide new strategies for treating lipid metabolism disorders.

Introduction: Hepatic steatosis is a hepatic pathological change closely associated with metabolic disorders, commonly observed in various metabolic diseases such as metabolic syndrome (MetS), with a high global prevalence. Dai-Zong-Fang (DZF), a traditional Chinese herbal formula, is widely used in clinical treatment for MetS, exhibiting multifaceted effects in reducing obesity and regulating blood glucose and lipids. This study aims to explore the mechanism by which DZF modulates the gut microbiota and reduces hepatic steatosis based on the gut-liver axis. Methods: This study utilized db/db mice as a disease model for drug intervention. Body weight and fasting blood glucose were monitored. Serum lipid and transaminase levels were measured. Insulin tolerance test was conducted to assess insulin sensitivity. Hematoxylin and eosin (HE) staining was employed to observe morphological changes in the liver and intestine. The degree of hepatic steatosis was evaluated through Oil Red O staining and hepatic lipid determination. Changes in gut microbiota were assessed using 16S rRNA gene sequencing. Serum lipopolysaccharide (LPS) levels were measured by ELISA. The expression levels of intestinal tight junction proteins, intestinal lipid absorption-related proteins, and key proteins in hepatic lipid metabolism were examined through Western blot and RT-qPCR. Results: After DZF intervention, there was a decrease in body weight, alleviation of glucose and lipid metabolism disorders, reduction in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and mitigation of insulin resistance in mice. DZF significantly modulated the diversity of the gut microbiota, with a notable increase in the abundance of the Bacteroidetes phylum. PICRUSt indicated that DZF influenced various functions in gut microbiota, including carbohydrate and amino acid metabolism. Following DZF intervention, serum LPS levels decreased, intestinal pathological damage was reduced, and the expression of intestinal tight junction protein occludin was increased, while the expression of intestinal lipid absorption-related proteins cluster of differentiation 36 (CD36) and apolipoprotein B48 (ApoB48) were decreased. In the liver, DZF intervention resulted in a reduction in hepatic steatosis and lipid droplets, accompanied by a decrease fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1) and fatty acid transport protein 2 (FATP2). Conversely, there was an increase in the expression of the fatty acid oxidation-related enzyme carnitine palmitoyltransferase-1𝛂 (CPT-1𝛂). Conclusion: DZF can regulate the structure and function of the intestinal microbiota in db/db mice. This ameliorates intestinal barrier damage and the detrimental effects of endotoxemia on hepatic metabolism. DZF not only inhibits intestinal lipid absorption but also improves hepatic lipid metabolism from various aspects, including de novo lipogenesis, fatty acid uptake, and fatty acid oxidation. This suggests that DZF may act on the liver and intestine as target organs, exerting its effects by improving the intestinal microbiota and related barrier and lipid absorption functions, ultimately ameliorating hepatic steatosis and enhancing overall glucose and lipid metabolism.

OBJECTIVE: Lipoprotein assembly and secretion in the small intestine are critical for dietary fat absorption. Surfeit locus protein 4 (SURF4) serves as a cargo receptor, facilitating the cellular transport of multiple proteins and mediating hepatic lipid secretion in vivo. However, its involvement in intestinal lipid secretion is not fully understood. In this study, we investigated the role of SURF4 in intestinal lipid absorption.
METHODS: We generated intestine-specific Surf4 knockout mice and characterized the phenotypes. Additionally, we investigated the underlying mechanisms of SURF4 in intestinal lipid secretion using proteomics and cellular models.
RESULTS: We unveiled that SURF4 is indispensable for apolipoprotein transport and lipoprotein secretion. Intestine-specific Surf4 knockout mice exhibited ectopic lipid deposition in the small intestine and hypolipidemia. Deletion of SURF4 impeded the transport of apolipoprotein A1 (ApoA1), proline-rich acidic protein 1 (PRAP1), and apolipoprotein B48 (ApoB48) and hindered the assembly and secretion of chylomicrons and high-density lipoproteins.
CONCLUSIONS: SURF4 emerges as a pivotal regulator of intestinal lipid absorption via mediating the secretion of ApoA1, PRAP1 and ApoB48.

Cycloheximide (CHX) has been used to reduce the flow of intestinal lymph and as a non-surgical tool to study drug absorption via the intestinal lymphatics. Pharmacokinetic information on the agent, and its relationship to effect and toxicity, have not been examined. The goal of this study was to provide pharmacokinetic data and link it to lymph-blocking and toxicological effects. Jugular-vein cannulated (JVC) adult Sprague-Dawley male rats were administered 0.5 mg/kg CHX by oral, intraperitoneal (ip), and intravenous routes followed by blood draws, and CHX was assayed using LC-MS/MS. Another four JVC rats were given peanut oil (2 mL/kg) without and then with CHX to measure effects on lipid absorption as a surrogate indicator of lymph flow. One-week later plasma biochemistry measures were obtained. The results indicated that CHX had a high clearance and volume of distribution, and oral absolute bioavailability of 0.47 with 0.5 mg/kg. CHX was associated with dose- and route-dependent pharmacokinetics. The relative bioavailability after ip doses was over 3. CHX had low plasma protein binding and minor urinary excretion. Metabolism appeared to be occur by oxidation and glucuronidation. Reductions in plasma lipids (24-40 %) were seen after 2.5 mg/kg orally with signs of inflammation and increased liver enzymes persisting for a week after the dose. CHX was associated with a reduction in lipid absorption after oral doses of 2.5 mg/kg, which seems to justify its use as a non-surgical tool to evaluate the lymphatic pathway of absorption of drugs. However, it also possesses hepatotoxicity, which should be taken into consideration in its use.