Differential transport of cholesterol and oleic acid in lymph lipoproteins: sex differences in puromycin sensitivity

Vahouny, George V.; Blendermann, E. M.; Gallo, Linda L.; Treadwell, C. R.

doi:10.1016/s0022-2275(20)39791-1

Cited by 32 publications

(4 citation statements)

References 32 publications

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“…The use of male rats is not expected to alter the current findings. From previous studies, the influence of gender on lymph lipid/lipoprotein transport appears minimal. − Following surgery and during the experimental period, rats were housed in individual metabolic cages. Rats were fasted overnight after surgery until up to 8 h postdose on the next day.…”

Section: Materials and Methodsmentioning

confidence: 99%

High-Density Lipoprotein Composition Influences Lymphatic Transport after Subcutaneous Administration

et al. 2020

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Interstitial administration (e.g., subcutaneous (SC) administration) of immunotherapies and vaccines within nanoparticles can improve access to lymph-resident immune cells, leading to enhanced efficacy and reduced off-target effects. Recently, endogenous high-density lipoproteins (HDLs) were found to return from peripheral tissue back to the systemic circulation via the lymphatic vessels and nodes. This suggests the potential utility of HDLs as biocompatible lymphatic-targeted therapeutic carriers. However, we have a limited understanding of the mechanisms that drive HDL uptake into peripheral lymphatics from the interstitium. This study investigated the influence of HDL physicochemical properties on lymphatic transport and lymph node (LN) retention of HDL after SC administration. A range of HDL particles was prepared and characterized. Sphere-shaped endogenous HDLs were isolated from biological fluids (rat lymph, rat plasma, and human plasma) and separated into two subclasses based on the density. Discoidal-shaped synthetic (reconstituted) HDLs (rHDLs) of similar sizes were assembled from lipids and apolipoprotein A-I. All HDLs had similar sizes of 10–20 nm and a slightly negative surface charge. All HDLs were radiolabeled with 3H-cholesteryl ester (3H-CE) and/or 14C-free cholesterol (14C FC) and administered SC into the hind leg of thoracic lymph-cannulated rats. The recovery of radiolabels in lymph, plasma, LN, and tissues was determined. From the interstitial injection site, all HDLs were preferentially transported into the lymph and not blood vessels as indicated by high lymph-to-plasma concentration ratios of the radiolabels (up to 100:1 during the absorption phase) and greater radiolabel recovery in LNs draining the injection site compared to the contralateral side. Several HDLs with unique composition demonstrated significantly higher lymphatic transport compared to other HDLs despite possessing similar physical properties, suggesting that HDL lymphatic transport is less influenced by physical properties. The LN retention of HDL was positively correlated to increasing the negative charge of HDL, which was related to surface composition. Overall, this study informs the optimal design of HDL-based nanoparticles to promote lymphatic targeting of immunotherapies and vaccines.

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Section: Materials and Methodsmentioning

confidence: 99%

High-Density Lipoprotein Composition Influences Lymphatic Transport after Subcutaneous Administration

et al. 2020

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“…An ultrastructural and biochemical study conducted by Mahley et al (251) showed that intestinal Golgi vesicles contain either CMs or VLDL particles, and that little mixing of particle size occurs, thus suggesting separate biosynthetic pathways for these lipoproteins. Further evidence is provided by Vahouny et al (252), who demonstrated that puromycin had no significant effect on the incorporation of radioactive leucine into VLDL peptides in male rats. In contrast, however, the incorporation of radioactive leucine into CM peptides was markedly inhibited.…”

Section: Assembly Of Intestinal Lipoproteinsmentioning

confidence: 96%

Intestinal lipid absorption and transport

Phan

Tso²

2001

Front Biosci

166

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The purpose of this review is to update the reader on our current knowledge of the digestion, uptake, and transport of dietary lipid. In particular, it discusses how intestinal lipid transporters may play a role in the uptake of lipids by the enterocytes, and how chylomicrons are formed in the enterocytes and packaged for export into the lymphatic system through exocytosis. The classification and properties of lipids is first described followed by a discussion of structured lipids and their role in human nutrition. Digestion of triacylglycerols takes place in the stomach aided by the enzyme gastric lipase. The origin and properties of lingual and gastric lipase are reviewed. Most digestion of triacylglycerols by pancreatic lipase occurs in the intestinal lumen. Similarly, digestion of cholesteryl ester and phospholipids also takes place in the intestinal lumen. This review describes in considerable detail the uptake of lipid digestion products by the enterocytes, particularly the role of recently identified lipid transporters. The intracellular trafficking and the resynthesis of complex lipids from the lipid digestion products are talked about, particularly within the context of the recently generated knockout mouse that lacks the key lipid reesterification enzymes. Finally, the mechanisms of the formation and secretion of chylomicrons is described and clinical disorders discussed.

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“…Our current studies are in general agreement with the previous studies. As indicated above, earlier studies showed that female rats had higher VLDL protein production than male rats (Vahouny et al, 1977;Vahouny et al, 1980). Furthermore, our recently published studies showed that female mice had lower lymphatic TG secretion than male mice, which could partly be due to the estrogen-mediated enhancement of vascular endothelial growth factor A (VEGF-A) signaling (Liu et al, 2021).…”

Section: Discussionmentioning

confidence: 88%

“…As intestinal cells produce larger lipoproteins when challenged with dietary lipid ( Nauli et al, 2006 ; Nauli et al, 2014 ), this factor alone can explain why men are more prone to producing larger intestinal lipoproteins. The notion that sex hormones can impact intestinal lipid absorption was initially proposed in the late 1970s by Vahouny et al (1977) , Vahouny et al (1980) . Their studies revealed that female rats exhibited higher VLDL protein production compared to that of male rats, even when both sexes were subjected to the same amount of dietary fat.…”

Section: Introductionmentioning

confidence: 99%

The effects of sex hormones on the size of intestinal lipoproteins

Nauli,

Phan,

Tso

et al. 2023

Front. Physiol.

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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.

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Differential transport of cholesterol and oleic acid in lymph lipoproteins: sex differences in puromycin sensitivity

Cited by 32 publications

References 32 publications

High-Density Lipoprotein Composition Influences Lymphatic Transport after Subcutaneous Administration

High-Density Lipoprotein Composition Influences Lymphatic Transport after Subcutaneous Administration

Intestinal lipid absorption and transport

The effects of sex hormones on the size of intestinal lipoproteins

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