糖尿病与反向胆固醇转运的关系

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"糖尿病中的逆转胆固醇转运" 本文是一篇关于糖尿病与胆固醇逆转运输关系的学术论文，由Eder C. R. Quintaão、Wilson L. Medina和Marisa Passarelli在Lipid Metabolism Laboratory (LIM 10)发表。研究主要探讨了糖尿病患者中胆固醇逆转运输（RCT）系统缺陷与早发性动脉粥样硬化之间的联系。胆固醇逆转运输是体内清除多余胆固醇的重要机制，特别是通过高密度脂蛋白（HDL）从外周组织向肝脏转移胆固醇，从而防止胆固醇在血管壁堆积，形成动脉粥样斑块。在正常情况下，HDL的亚组分、胆固醇酯转移蛋白（CETP）以及卵磷脂胆固醇酰基转移酶（LCAT）的活性对RCT过程至关重要。然而，糖尿病患者（DM）的动脉粥样硬化情况往往更为严重。尽管RCT系统的重要性已被广泛认识，但这篇论文指出，在糖尿病患者中，动脉壁细胞对修饰过的载脂蛋白B（apoB）包含的脂蛋白摄取增加可能是主要原因。这种修饰可能包括氧化或糖基化等，导致脂蛋白更容易被细胞识别和摄取，进而促进动脉壁的炎症反应和斑块形成。糖尿病患者的代谢异常，如血糖控制不良，可能导致脂质代谢紊乱，进一步影响RCT系统的功能。例如，糖尿病可能降低HDL的抗氧化能力，改变CETP活性，或影响LCAT的表达和活性。这些变化可能促进动脉粥样硬化的进展，并增加心血管疾病的风险。此外，论文还可能探讨了糖尿病患者RCT途径的具体病理生理机制，可能包括炎症因子、氧化应激、胰岛素抵抗等因素如何干扰这一过程。同时，作者可能提出了针对这些机制的干预策略，如改善血糖控制、增加HDL功能、抑制CETP活性或提高LCAT活性，以期在糖尿病患者中恢复或增强RCT，从而预防或延缓动脉粥样硬化的进程。这篇论文深入研究了糖尿病背景下胆固醇逆转运输的障碍及其在动脉粥样硬化形成中的作用，为理解和治疗糖尿病相关心血管疾病提供了新的视角。

membrane is esteri®ed in the HDL particles by the enzyme,

lecithin-cholesterol acyl transferase (LCAT), bringing on

modi®cation of the composition and shape of HDL [49].

HDL initially takes on a disk-like shape (preb-2 HDL) and,

as cholesteryl-ester accumulates, a near spherical form

(aHDL) is attained where changes of the core and surface

domains in¯uence the function of the lipoprotein. LCAT

activity controls the cellular cholesterol ef¯ux by creating

a gradient of unesteri®ed cholesterol from the cell

membrane down to the aHDL particle [50]. Also, the

LCAT activity inhibits the unesteri®ed cholesterol re-

uptake by cells [51]. Furthermore, the cellular enzyme,

acyl-cholesterol acyltransferase (ACAT), is also involved in

the ef¯ux through regulation of the cell membrane content

of the non-esteri®ed cholesterol available for disposal

[52].

Cellular mechanisms controlling the

ef¯ux of cholesterol

Cell cholesterol ef¯ux takes place by passive and active

mechanisms. The former is related to the diffusion of

unesteri®ed cholesterol across the water layer between

cells and the acceptor particles.

Lipid composition of the cell membrane as well as of

the HDL particles are the major determinants for the

cholesterol desorption from plasma cell membranes since

it depends on a cholesterol gradient between cell

membrane and acceptor LP. Also, steroid-transporter

molecules, whose gene has recently been cloned, seem to

have a role in the intracellular cholesterol traf®c [53].

HDL composition also interacts with the activities of

LCAT, CETP and phospholipid transfer protein (PLTP).

Recent studies have shown that the class B scavenger

receptors type I and type II (SR-BI and SR-BII) play

important roles in the ¯ux of cholesterol in cells [54±57].

SR-BI and SR-BII are alternatively spliced products from a

single gene [58] and are multi-ligand LP receptors that

bind HDL, LDL, modi®ed LP (as oxidized LDL) and

anionic phospholipids.

The expression of SR-BI is positively related to the

cholesterol ef¯ux in many cells [54±55]. It has been

assumed that SR-BI is mainly related to a passive

mechanism that drives the cholesterol diffusion to the

phospholipid-containing acceptor particle [55]. Evidence

for this comes from studies with cells that express high

levels of SR-BI and have elevated rates of cholesterol

ef¯ux. Conversely, these cells are not responsive to the

process of cholesterol removal mediated by apo A-I even

though this apolipoprotein binds to the receptor [56].

Also, SR-BI localization with caveolin-1 in caveolar

domains sheds light on a role of this receptor in lipid

redistribution in cell membranes, which could favor a

bidirectional ¯ux of cholesterol [57]. It has also been

demonstrated that the SR-BI receptor mediates the

selective uptake of HDL-CE characterizing the last

phase of the RCT in the liver. This event occurs by a

transient binding of HDL to the receptor, without

apolipoprotein internalization. The selective transport

of lipids from HDL is also the major pathway by which

cholesterol is provided to steroidogenic cells [58]. Animal

models lacking SR-BI have increased cholesterol plasma

levels as well as diminished adrenal gland cholesterol

content [58]. In this regard adenovirus-mediated over-

expression of SR-BI in mouse is associated with a drastic

reduction of plasma HDL [59]. Since PL-HDL is the major

determinant of cholesterol traf®cking mediated by SR-BI,

we should address the role on the SR-BI function of the

compositional changes in HDL that take place in DM

[60,61].

Mendez et al. [52] suggested that the cell cholesterol

ef¯ux is an active energy-dependent process where lipid-

poor apolipoproteins, mainly apoA-I, interact with plasma

membrane components eliciting intracellular signals that

target cholesterol to the cell membrane. Tangier disease

(TD) is a rare autosomal recessive disorder characterized

by extremely low levels of HDL-cholesterol in plasma,

deposition of CE in the reticulo-endothelial cells and

altered cellular lipid traf®cking. Nonetheless, considering

their low LDL-cholesterol levels in plasma, TD patients

have a modest risk of atherosclerosis. It has been shown

that ®broblasts from TD patients lack the apo A-I

mediated cholesterol ef¯ux pathway [62].

Recently, different mutations in the ABCA-1 gene have

been detected in patients with TD [63±65]. This gene

codi®es to an ABCA-1 transporter molecule which is a

member of the ATP-binding cassette transporter family

that utilizes ATP hydrolysis to transport several molecules

across the membrane. ABCA-1 levels are positively

regulated in cells by cholesterol loading and by cyclic

AMP treatment and, inversely, by HDL and apo A-I [66].

Fibroblasts isolated from target null ABCA-1 mice show

low levels of lipid removal mediated by apo A-I in a

similar pattern to that observed in ®broblasts from TD

patients. Conversely, ABCA-1 overexpression restores

the cell cholesterol and phospholipid removal capacity

[62]. ABCA-1 transporters shuttle between the Golgi

complex and the plasma membrane and can operate like a

channel that exports cholesterol to apo A-I. Taking into

account the fact that ABCA-1 has a crucial role in cellular

lipid removal, the elucidation at a molecular level

of the factors that control its expression and function

should be useful in targeting pharmacological therapies to

atherosclerosis.

Integrated roles in cell cholesterol

removal of CETP, PLTP and the

enzymes LCAT and lipoprotein

lipases

Cholesteryl-ester enriched HDL produced by LCAT

activity carries on the cholesteryl-ester transfer process

mediated by the cholesteryl-ester transfer protein (CETP)

[50]. CETP is a hydrophobic glycoprotein, 66±74 kDa

molecular weight, that redistributes cholesteryl-ester,

Reverse Cholesterol Transport in DM 239

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