9E Health-Promoting Effects of Wine Phenolics 577
NADPH oxidase activity in circulating neutrophils (unpublished observations).
NADPH oxidase-dependent superoxideproduction appears to be abnormally high in
mononuclear cells from these patients (Fortu ̃no et al. 2005). The absence of a com-
mercial pharmacological treatment to reduce or inhibit systemic NADPH oxidase
enzyme complex highlights the importance of our results, which demonstrate for
the first time that the oxidative stress produced by systemic NADPH oxidase may
be counteracted by supplementation with polyphenols. Our in vitro studies suggest
that the mechanism involved in this effect is the reduction of p22phox, p47phox,
and NOX expression (unpublished observations).
9E.4 Effects on Lipid Metabolism
More than 93% of the body’s cholesterol is located within the cells, where it plays
various structural and metabolic roles. The rest circulates in the plasma within the
lipoprotein particles. Given the link between plasma cholesterol level and cardiovas-
cular diseases, the regulation of cholesterol homeostasis is of great interest. Choles-
terol homeostasis depends on a highly regulated balance between the absorption
of dietary cholesterol, de novo cholesterol biosynthesis, and biliary clearance and
excretion. Familial hypercholesterolemia is one of the most common disorders of
cell cholesterol homeostasis and is caused by a mutation in the gene encoding the
LDL receptor. Plasma LDL binds to the receptor and is taken into cells to sup-
ply cholesterol for vital cellular functions. Defects in the LDL receptor lead to
an increase in the plasma concentration of LDL-cholesterol, which may deposit in
arteries and promote atherosclerosis. Onthe other hand, excess intracellular choles-
terol induces cytotoxicity and apoptosis (Feng et al. 2003). ABC transporters are
a large family of proteins that transport different molecules across the cell mem-
brane (Kaminski et al. 2006). Several ABC transporters are involved in cholesterol
efflux from cells. ABCA1 and ABCG1 are implicated in the reversal of cholesterol
transport to Apo A-I rich particles, and ABCG5 and ABCG8 are implicated in the
efflux of plant sterols to the intestinal lumen from enterocytes, as well as in bile acid
excretion in the liver (Oram and Vaughan 2006). Mutations in either ABCG5 or
ABCG8 produce the rare autosomal recessivedisease called sitosterolemia, result-
ing in hyperabsorption of plant sterols (Berge et al. 2000). Mutations in ABCA1 lead
to Tangier disease, characterized by cholesterol accumulation in macrophages and
reduction of circulating mature HDL (Clee et al. 2000). In cultured macrophages,
anthocyanins and various polyphenols induce cholesterol efflux and ABCA1 expres-
sion (Xia et al. 2005). These effects have been reported to be due, at least in part, to
the activation of liver x receptor (LXR ) and associated changes in gene expres-
sion (Sevov et al. 2006; Xia et al. 2005; 2007). The nuclear receptor LXR is acti-
vated by oxysterols and is involved in regulating the metabolism of cholesterols and
bile acids. It limits cholesterol accumulation through the expression of the choles-
terol efflux genes ABCA1, ABCG1, ABCG5, and ABCG8. LXR- also serves
as a molecular link between cholesterol metabolism and inflammation (Tontonoz