**4. Effects of taurine on atherogenesis/development of atherosclerosis**

High blood cholesterol levels is the most pronounced risk factor for developing atherosclerosis, vascular inflammation and hardening of the arteries associated with excess cholesterol deposition in the vasculature. Apart from humans and monkeys, wild animals normally do not develop substantial atherosclerosis. There is however, an array of laboratory animal models in common use for studying the effects of pharmacological substances and dietary modifications on lesion formation. The effect of taurine has been investigated in several of these models.

### **4.1. Effects of taurine on atherosclerosis in mice**

278 Lipoproteins – Role in Health and Diseases

HDL (LDL+VLDL) cholesterol.

profiles is due to increased cholesterol metabolism.

*3.1.5. Effects of taurine on cholesterol levels in humans* 

potential of taurine as a hypocholesterolemic agent.

drinking water (1% w/v) reduced serum total cholesterol in chow- (15% reduction) as well as high-fat diet-fed (42% reduction) hamsters [102]. A similar effect was observed for non-

Recently, lipid metabolism has been closely studied in Male Golden Syrian Hamsters fed different diets with or without taurine for 4 weeks [103]. The groups received a high fat diet (chow mixed with 7% butter [w/w] and 0.2% cholesterol [w/w]) and drinking water without or supplemented with either 0.35% or 0.7% taurine (w/v). Hamsters given taurine was smaller, had less visceral fat and smaller livers after 4 weeks. Both taurine concentrations resulted in significant lower serum triglycerides, total cholesterol, and LDL+VLVL cholesterol. Up-regulated gene expression of the low-density lipoprotein receptor and CYP7A1 genes, paralleled by increased faecal cholesterol and bile acid concentrations in the taurine treated hamsters, indicated that the taurine effect on the cholesterol and lipid

Historically, taurine has been believed to decrease blood cholesterol levels in adults. Only a limited number of studies have investigated the effect of oral taurine supplementation on blood cholesterol or lipoprotein levels in humans and ambiguous results have arisen from these. Early studies found no effect on serum cholesterol after incidental treatment of patients with 1.5 to 3 g taurine/day for up to 2 months [77, 104, 105]. To our knowledge there has been no well-designed random controlled clinical trial assessing the doseresponse effect of oral taurine supplementation on blood lipids in healthy humans. However, the effect of taurine in relation to development of CVD has been documented through a human clinical trial. Results of a 7 week human intervention trial revealed that supplementation with 0.4 g taurine/day in combination with omega-3 fatty acids (1 g EPA+DHA/day) significantly improved the lipid profiles by reducing serum total and LDL cholesterol levels compared to supplementation with omega-3 fatty acids alone [106]. In another study the effects of oral supplementation with taurine (3 g/day) or placebo for 7 weeks was assessed in young obese healthy subjects [107]. In this study, taurine had no effect on serum cholesterol, but triglycerides and bodyweight was significantly reduced compared to placebo effect. Finally, a daily 6 g taurine supplementation to human healthy volunteers receiving a cholesterol-inducing diet for 3 weeks attenuated the expected increase of serum total cholesterol and LDL-cholesterol, whereas serum VLDL-cholesterol and triglyceride levels compared to the control group [108]. In insulin-dependent diabetes mellitus patients intake of taurine (1 g/day) reduced serum triglyceride levels, but no effect was observed on serum cholesterol [109]. Finally, in a randomized, double-blinded, crossover intervention, overweight non-diabetic men given a daily dose of 1.5 g taurine or placebo, no effect was reported on blood lipids [71]. In summary, results from oral taurine supplementation to humans are ambiguous, and further adequately designed interventions are warranted to further investigate the In the hyperlipidemic apoE-/- mice, taurine has been reported to delay atherogenesis by decreasing oxidized substances that cause inflammation, as well as increasing HDLcholesterol [82]. Also in apoE-/- mice fed a normal rodent chow supplemented with 2% taurine (w/w) for 12 weeks, formation of atherosclerotic lesions were significantly reduced [81]. However this effect was independent of serum cholesterol as VLDL, LDL, and total cholesterol were increased.

Moreover, in spontaneously hyperlipidemic mice, taurine (1% w/v) provided through drinking water, was reported to suppress the development of lesion formation without affecting the levels of serum VLDL and LDL [82].

In our lab, apoE-/--mice were given Western diets (WD) containing 20% fat (w/w), 0.2% cholesterol (w/w) for 13 weeks [110]. The mice received WD, WD supplemented with 0.5% taurine (w/w) or WD supplemented with 0.5% taurine (w/w) in combination with a daily dose of marine long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA) recommend in the dietary guidelines for humans. In these studies, taurine did not affect serum cholesterol or triglyceride levels alone or combination with n-3 PUFA. This may indicate that a larger supplementary dose of taurine is needed to prevent dietary induced hypercholesterolemia in apoE-/--mice.

#### **4.2. Effects of taurine on lipid lesion formation in rats**

Rats are generally not a suitable animal model for atherosclerosis as they do not develop lesion deposits resembling the early phase of human atherogenesis. However, in a rat model of balloon induced vascular neointima formation, supplementation with taurine (3% in drinking water) from 2 days before the surgical procedure and 14 days after, reduced vascular smooth muscle cell proliferation [111]. This key step in the initiation of atherogenesis was reduced by 28% compared to control fed rats. Taurine was located immunohistochemically mainly to the surface of the exposed media and adventitia of the injured carotid artery and higher levels were observed in the taurine treated rats. This corresponded to a lower vascular production of superoxide anion compared to the control animals. From these experiments it was concluded that the preventive effect of taurine towards neointima formation was attributable to anti-oxidative effects.

#### **4.3. Effects of taurine on atherosclerosis in rabbits**

The effect of dietary taurine on development of atherosclerosis has been investigated in different rabbit strains. Taurine has been indicated to prevent progression of atherosclerotic lesions in rabbits without affecting serum cholesterol in two different models. In New-Zealand white male rabbits given a diet containing 2% cholesterol (w/w), taurine added to the drinking water (0.1 or 0.5% w/v) for 14 weeks reduced the aortic deposition of fat [97]. This so-called anti-atherosclerotic effect was only significant for the highest taurine dose tested. Recently, it was indicated that the taurine antiatherosclerotic effect was evident in these rabbits after only 4 weeks on the atherogenic diet [100]. *Watanabe heritable hyperlipidemic (WHHL) rabbits* carries an inheritable mutation in the LDL receptor and is hence a typical genetically hyperlipidemic animal model. When WHHL rabbits were given drinking water containing 1% taurine (w/v) for 6 months they developed significantly less atherosclerotic lesion formation compared to rabbits not supplemented with taurine [112].

#### **4.4. Effects of taurine on atherosclerosis in humans**

Results on the effects of dietary taurine in humans are mainly from prospective studies. It is evident that individuals with high urinary excretion of taurine and high dietary intake of food high in taurine in general have fewer incidences of cardiovascular diseases compared to individuals with low dietary intake of taurine [33]. In addition, increased dietary intake of taurine either alone or in the combination with omega-3 fatty acids, has also been suggested to reduce MCP-1, an important risk factor of CVD [106]. No further randomised clinical trials on the effects of dietary supplementation of taurine on CVD disease markers has been reported.
