**3. Hypercholesterolemia induced by food restriction is associated with autophagy induction**

of atherosclerosis, dietary change is considered an important strategy in the prevention of atherosclerosis [2]. Moreover, dietary modification has shown to play an important role in several age-associated pathologies and in aging itself. Moderate calorie restriction results in a lifespan expansion of different species including yeast, fruit flies, nematodes, fish, rodents, and rhesus monkeys [3]. Besides favorable effects on longevity, long-term as well as short-term caloric restriction improves the cardiovascular disease risk profile in humans [4, 5]. Consistent with this finding, animal studies showed that dietary restriction attenuates atherosclerotic plaque

Starvation, as an extreme form of food restriction, is also one of the most important stimuli for autophagy induction [8]. Autophagy is a subcellular degradation pathway for long-lived proteins and damaged organelles. Under normal conditions, autophagy is a homeostatic process that is found in all cell types. However, under stress conditions, it functions as an important cell survival mechanism through nutrient recycling and the generation of energy [9]. Growing evidence indicates that autophagy deficiency plays a crucial role in plaque growth and destabilization [10–12]. Moreover, autophagy induction is suggested as a novel strategy for the

Cholesterol withdrawal by feeding atherosclerotic rabbits a normal diet for 4 weeks significantly reduces LDL cholesterol in serum (**Table 1**). In contrast, cholesterol withdrawal by severe food restriction (only 20% of normal diet) leads to elevated LDL cholesterol levels and a significant loss of bodyweight (**Table 1**), which confirms previous studies showing hypercholesterolemia in healthy subjects after fasting or moderate caloric restriction [15–17] as well as in patients with eating disorders such as anorexia nervosa [18]. Several mechanisms may account for hypercholesterolemia including downregulation of the hepatic LDL receptor leading to decreased LDL uptake in the

**Weeks Baseline Normal diet Restricted diet**

24 / 250 ± 105## 1101 ± 177#, \*\*\*

24 / 4.4 ± 0.1 3.2 ± 0.1###, \*\*\*

24 / 49 ± 7 44 ± 9

**Table 1.** Serum lipid values and body weight in cholesterol-fed rabbits (baseline, 20 weeks of cholesterol) followed by

development and decreases endothelial dysfunction [6, 7].

62 Atherosclerosis - Yesterday, Today and Tomorrow

prevention and treatment of atherosclerosis [13, 14].

Data are expressed as mean ± SEM.

###P < 0.001 versus 20 weeks (paired sample t-test, n = 10). \*\*\*P < 0.001 versus normal diet (independent sample t-test, n = 10).
