*3.1.2. Effects of taurine on cholesterol levels in rats*

A large number of studies have investigated the effect of dietary taurine on dietary hypercholesterolemia in various rat models [65]. Rats fed high-fat diets seem to be the model with most consistent antihypercholesterolemic effects of dietary taurine. Rats have a relatively low taurine content in skeletal muscles (10-25 mg/100 g muscle) [83, 84].

Rats are generally not suitable for pharmacologically cholesterol and lipoprotein studies due to their substantially different lipid profile compared to humans.

*Male wistar rats.* Taurine supplementation does not alter plasma lipids in male wistar rats fed normal chow [85]. However, when these rats were fed high cholesterol diet containing 2% cholesterol and 1% cholic acid, dietary supplementation of 4% taurine significantly counteracted the observed increase in serum cholesterol by 44% [86]. This observation has been confirmed be several studies [87-90]. In Wistar male rats fed a cholesterol-containing diet (0.5% cholesterol w/w) for 40 days, serum cholesterol increased 5 fold compared to chow fed rats. Oral supplementation of 470 mg/kg/day taurine (0.5% w/v) in water lowered the increased serum cholesterol (54%) [91]. When these rats were fed a high-fat diet (11% coconut oil w/w) for 6 months, a daily oral supplementation of 1 mg taurine lowered serum cholesterol (37%), LDL cholesterol (34%), and triglycerides (95%), compared to the high-fat control diet [88]. Already after 14 days intervention, 5% dietary taurine (w/w) supplementation has been indicated to lower high cholesterol (1% cholesterol, 2.5% cholate) induced serum cholesterol (- 42%) [90]. In wistar rats, the taurine effect has been indicated to be caused by an increased faecal bile acid excretion, increased hepatic cholesterol 7α-hydroxylase expression and activity [89, 90]. The rapid effect of taurine supplementation on serum cholesterol has been confirmed recently [92]. When fed a diet containing 60.7% sucrose, 9.0% lard, and 0.5% cholesterol for 14 days, serum cholesteryl ester and free cholesterol were reduced by 39% and 53% compared to rats fed control diet without taurine, respectively. Rats fed taurine also had smaller livers compared to control-fed rats. Hepatic cholesteryl esters were also reduced by approximately 20% in the taurine supplemented rats. This hypocholesterolemic effect was ascribed to a lower hepatic secretion of cholesteryl esters.

*Streptozotocin-induced diabetic rats*. Male Wistar rats injected with STZ are also used as a diabetic model. In these rats dietary taurine supplementation markedly reduced serum total cholesterol (-50%) induced by cholesterol-containing diet (1% cholesterol w/w) for 4 weeks [93].

*Fructose-induced rat insulin resistance model.* Male wistar rats fed a diet containing 60% fructose developed impaired glucose tolerance and insulin resistance [85]. Taurine administration (300 mg/kg/day *i.p.*) counteracted the fructose induced plasma total cholesterol, LDL cholesterol, and triglycerides by 11%, 21%, and 23%, respectively.

*Spontaneously hypertensive rats (SHR).* The effect of taurine supplementation on blood pressure in SHR rats was investigated already in the 1970ies [94]. How dietary administration of taurine affects cholesterol metabolism has not been reported in these studies. However, in a stroke-prone substrain of the SHR rats, taurine supplementation has been indicated to prevent high-fat/high cholesterol induced elevation of serum cholesterol in SHR rats [95].

*Sprague-Dawley rats.* Also in male Sprague-Dawley rats fed a high-fat, high cholesterol diet (HFCD; 10% corn oil, 1.5% cholesterol) supplemented with taurine (1.5% w/w) plasma cholesterol was lowered by 31% compared to HFCD control rats [87]. LDL+VLDL cholesterol (-38%) and triglycerides (-43%) were also lower in rats supplemented with taurine compared to HFCD control rats. These results have been confirmed with an identical experimental setup for 5 weeks reporting a 20% and 25% reduction in serum total cholesterol and triglycerides, respectively [96]. In this model, plasma total cholesterol, LDL cholesterol and triglycerides were reduced in rats fed taurine supplemented cholesterol free diet compared the cholesterol free control diet [87].

#### *3.1.3. Effects of taurine on cholesterol levels in rabbits*

276 Lipoproteins – Role in Health and Diseases

cholesterol levels [82].

*3.1.2. Effects of taurine on cholesterol levels in rats* 

hepatic secretion of cholesteryl esters.

[93].

In more extreme models such as apolipoprotein E-deficient (apoE-/-) mice fed a normal rodent chow supplemented with 2% taurine (w/w) for 12 weeks, serum VLDL, LDL and total cholesterol levels increased compared to mice without taurine supplementation [81]. Similar results has been reported for extreme spontaneously hyperlipidemic mice (SHL; KOR-*Apoeshl*), where 12 weeks treatment with 1% taurine (w/v) added to the drinking water increased serum HDL-cholesterol but did not affect serum total cholesterol or VLDL+LDL

A large number of studies have investigated the effect of dietary taurine on dietary hypercholesterolemia in various rat models [65]. Rats fed high-fat diets seem to be the model with most consistent antihypercholesterolemic effects of dietary taurine. Rats have a

Rats are generally not suitable for pharmacologically cholesterol and lipoprotein studies due

*Male wistar rats.* Taurine supplementation does not alter plasma lipids in male wistar rats fed normal chow [85]. However, when these rats were fed high cholesterol diet containing 2% cholesterol and 1% cholic acid, dietary supplementation of 4% taurine significantly counteracted the observed increase in serum cholesterol by 44% [86]. This observation has been confirmed be several studies [87-90]. In Wistar male rats fed a cholesterol-containing diet (0.5% cholesterol w/w) for 40 days, serum cholesterol increased 5 fold compared to chow fed rats. Oral supplementation of 470 mg/kg/day taurine (0.5% w/v) in water lowered the increased serum cholesterol (54%) [91]. When these rats were fed a high-fat diet (11% coconut oil w/w) for 6 months, a daily oral supplementation of 1 mg taurine lowered serum cholesterol (37%), LDL cholesterol (34%), and triglycerides (95%), compared to the high-fat control diet [88]. Already after 14 days intervention, 5% dietary taurine (w/w) supplementation has been indicated to lower high cholesterol (1% cholesterol, 2.5% cholate) induced serum cholesterol (- 42%) [90]. In wistar rats, the taurine effect has been indicated to be caused by an increased faecal bile acid excretion, increased hepatic cholesterol 7α-hydroxylase expression and activity [89, 90]. The rapid effect of taurine supplementation on serum cholesterol has been confirmed recently [92]. When fed a diet containing 60.7% sucrose, 9.0% lard, and 0.5% cholesterol for 14 days, serum cholesteryl ester and free cholesterol were reduced by 39% and 53% compared to rats fed control diet without taurine, respectively. Rats fed taurine also had smaller livers compared to control-fed rats. Hepatic cholesteryl esters were also reduced by approximately 20% in the taurine supplemented rats. This hypocholesterolemic effect was ascribed to a lower

*Streptozotocin-induced diabetic rats*. Male Wistar rats injected with STZ are also used as a diabetic model. In these rats dietary taurine supplementation markedly reduced serum total cholesterol (-50%) induced by cholesterol-containing diet (1% cholesterol w/w) for 4 weeks

relatively low taurine content in skeletal muscles (10-25 mg/100 g muscle) [83, 84].

to their substantially different lipid profile compared to humans.

Different rabbit strains have been used to investigate the effects of dietary taurine supplementation on dietary induced hypercholesterolemia [86, 97, 98]. The results from the administration of taurine to rabbits have been ambiguous. In *Male New Zealand white rabbits*, fed a high cholesterol (1% w/w) diet, addition of 2.5% taurine (w/w) for 2.5 month reduced the serum total cholesterol and triglyceride levels by 22% and 38%, respectively, compared to high cholesterol diet alone [99]. In this study similar reductions were observed for hepatic and aorta lipid levels in these rabbits. However, when the same rabbit strain were given normal chow supplemented with 0.5% cholesterol (w/w) for 4 weeks no effect of dietary taurine (2.5% w/w) supplementation was observed [100]. Also when given a normal diet supplemented with 2% cholesterol (w/w), taurine added to the drinking water (0.1 or 0.5% w/v) for 14 weeks had no influence on serum cholesterol and triglycerides [97].

#### *3.1.4. Effects of taurine on cholesterol levels in hamsters*

Hamsters (Male Golden Syrian hamsters) have also been used as model for studying cholesterol metabolism. The rationale for this is that hamsters and humans have comparable blood cholesterol levels, hamsters use both taurine and glycine for bile acid conjugation and the lipoprotein profile in response to dietary cholesterol is comparable [101]. When Male Golden Syrian hamsters were fed a normal chow supplemented with 0.05% cholesterol or a 10% coconut oil, high-fat diet (0.05% cholesterol) for two weeks, taurine dissolved in

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-HDL (LDL+VLDL) cholesterol.

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 profiles is due to increased cholesterol metabolism.

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

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 potential of taurine as a hypocholesterolemic agent.
