578 A. D ́avalos and M. A. Lasunci ́on
and Mangelsdorf 2003). Interestingly, anthocyanins have been reported to mod-
ify cholesterol distribution in lipid rafts in endothelial cells, possibly by activating
ABCA1-mediated cholesterol efflux, which prevents the recruitment of TRAF-2 to
lipid rafts and thus inhibits the CD40-CD40L inflammatory pathway associated with
NFB (Xia et al. 2007).
Cholesterol homeostasis is characterized by a feedback regulation achieved
through the membrane-bound sterol regulatory element-binding protein (SREBP)
family of transcription factors (Brown et al. 2000). SREBPs are synthesized as
inactive precursor proteins and anchored to the endoplasmic reticulum (ER), where
they interact with the SREBP-cleavage-activating protein (Scap). Insigs proteins
are resident in the ER and interact withScap, retaining the SREBP/Scap com-
plex in the ER while Scap binds cholesterol. Scap possesses a sterol-sensing
domain. In response to low cellular cholesterol levels, a conformational change
in the Scap protein is induced and Scap is released by Insig. It then escorts the
SREBPs to the golgi, where they are processed by two membrane-associated pro-
teases (S1P and S2) that cleave at a site in the lumen (S1P) and a site within
the first transmembrane domain of SREBPs, liberating the active SREBP frag-
ment (Brown et al. 2000). The active fragments translocate to the nucleus, where
they bind to the promoter of the different genes regulated through the SREBPs
(Goldstein et al. 2006). Target genes regulated by SREBPs include the LDL recep-
tor, 3-hydroxy-3-methylglutaryl coenzyme A reductase (the rate limiting enzyme
in de novo cholesterol biosynthesis), several genes involved in the synthesis and
metabolism of sterols, and embryonic signaling proteins. Lowering plasma choles-
terol by reducing intestinal absorption,raising LDL receptor expression, reduc-
ing de novo biosynthesis, increasing reverse cholesterol transport, or promoting
cholesterol elimination through the biliarysystem is of great interest to prevent
atherosclerosis.
The first reported beneficial effects of wine intake on lipid metabolism were those
concerning its antioxidant activity against LDL oxidation. Oxidative modification
of LDL in the arterial wall plays a key role in the pathogenesis of atherosclerosis
(Witztum and Steinberg 1991). Polyphenols from grapes have been demonstrated
to inhibit both in vitro and ex-vivo LDL oxidation and lipid peroxidation, after
ingestion of different wine or grape juice types, for different periods of time or
in different amounts (Abu-Amsha et al. 2001; Aviram and Fuhrman 1998;Castilla
et al. 2006; Frankel et al. 1993; Hayek et al. 1997; Ivanov et al. 2001; Nigdikar
et al. 1998; O’Byrne et al. 2002; Pignatelli et al. 2006b; Stein et al. 1999). A
plausible mechanism to explain this effect is through sparing of endogenous alpha-
tocopherol content of LDL, thereby avoiding LDL oxidation (Deckert et al. 2002;
Frank et al. 2006), and preservation or increase of paraoxonase activity (Fuhrman
and Aviram 2002; Gouedard et al. 2004). Human paraoxonases are serum HDL-
associated enzymes that can hydrolyze and reduce lipid peroxides in lipoproteins
and arterial cells. Consumption of wine polyphenols and other sources of polyphe-
nols reduces total plasma cholesterol and/or LDL cholesterol, both in healthy
subjects (Cartron et al. 2003; Castilla et al. 2006; Zern et al. 2005) and dif-
ferent groups with varying health status, including hypercholesterolemic subjects