Plasma clearance and net uptake of α-tocopherol and low-density lipoprotein by tissues in WHHL and control rabbits

Abstract

The mechanism(s) of uptake of vitamin E (alpha-tocopherol) by tissues is poorly understood. It has, however, been suggested from studies in vitro that the apolipoprotein B/E (apo B/E) receptor pathway for low-density lipoprotein (LDL) may be involved. To investigate the role of the apo B/E receptor pathway in vivo, we have studied the transport and uptake of alpha-tocopherol by tissues in Watanabe Heritable Hyperlipidaemic (WHHL) rabbits, which lack functional LDL (apo B/E) receptors, and controls. [3H]alpha-Tocopherol incorporated within LDL labelled with [14C]sucrose was used in these studies, as this enabled the uptake of both alpha-tocopherol and LDL to be studied independently. The principal findings were as follows. (1) Concentrations of the circulating lipids (including alpha-tocopherol) and LDL were increased and the plasma fractional disappearance rates of alpha-tocopherol and LDL decreased in the WHHL rabbits. (2) The WHHL rabbits clear more LDL and alpha-tocopherol from the circulation than controls do, because of their increased pool sizes of alpha-tocopherol and LDL. (3) The lipoprotein composition of the WHHL rabbits differed from that of the controls, and there was exchange of alpha-tocopherol between the lipoprotein fractions in vivo and in vitro. (4) High-affinity apo B/E receptors were not essential for the uptake of alpha-tocopherol by tissues. (5) Evidence from the plasma-clearance and tissue data suggest that alpha-tocopherol can be taken up by tissues in association with, and also independent of, LDL. We conclude that there are several different mechanisms for the uptake of alpha-tocopherol by tissues, which include receptor-dependent and receptor-independent pathways, independent transport and co-transport of alpha-tocopherol and LDL, and uptake from a number of different lipoproteins.

Intracellular trafficking of vitamin E in hepatocytes: the role of tocopherol transfer protein

“…These results confirm and extend previous reports suggesting that SR-BI-mediated uptake of vitamin E from HDL is physiologically important (21,29). This notion is also supported by the observations that in vivo, disruption of SR-BI expression causes a reduction in tocopherol levels (39), whereas defects in the LDL receptor do not impact tissue uptake of vitamin E (40). Furthermore, our data demonstrate that TTP is not essential for tocopherol uptake from LDL or HDL in hepatocytes.…”

Cellular mechanisms of vitamin E uptake: relevance in α-tocopherol metabolism and potential implications for disease

“…In this animal model, a significant decrease in LDL ␣-tocopherol clearance, paralleling the inherent holoparticle clearance defect, was found [31]. Remarkably, WHHL rabbits exhibited no overt defect in tissue ␣-tocopherol levels except for a mild reduction in adrenal ␣-tocopherol content [32].…”

“…The physiological relevance of this pathway for in vivo ␣-tocopherol transport was assessed in LDLR-deficient Watanabe heritable hyperlipidaemic (WHHL) rabbits [31,32]. In this animal model, a significant decrease in LDL ␣-tocopherol clearance, paralleling the inherent holoparticle clearance defect, was found [31].…”

Complexity of vitamin E metabolism

“…Kono et al [76] suggested recently that LDL particles carry the major portion of plasma α-TOH and that LDLR-mediated endocytosis contributes significantly to the uptake of α-TOH into cells [77] . However, studies performed on apolipoprotein B (Apob)-knockout mice and heritable hyperlipidemic Watanabe rabbits lacking the LDLR showed discrepancies in circulating α-TOH levels and tissue distribution, thus questioning the importance of LDL for α-TOH transport [78,79] . Cohn et al [79] therefore concluded that α-TOH in LDL can be taken up by tissues via LDLR but is also independent of this lipoprotein receptor.…”

“…However, studies performed on apolipoprotein B (Apob)-knockout mice and heritable hyperlipidemic Watanabe rabbits lacking the LDLR showed discrepancies in circulating α-TOH levels and tissue distribution, thus questioning the importance of LDL for α-TOH transport [78,79] . Cohn et al [79] therefore concluded that α-TOH in LDL can be taken up by tissues via LDLR but is also independent of this lipoprotein receptor. Uptake transporters and specific intracellular transport proteins involved in α-TOH trafficking are handled in more detail in a following section.…”