Fatty liver is a common cause of chronic liver disease and refers to accumulation of excess fat in the liver. It is diagnosed that if fat exceeds 5% of the total weight of normal liver or when more than 30% of the hepatocytes in a liver lobule have lipid deposits, most of the fat that accumulates in the liver is triacylglycerols and fatty acids; other forms of fat, such as cholesterol, cholesterol ester, and phospholipids, are also present. Fatty liver is often associated with alcoholic liver disease, hyperinsu-linemia, and insulin-resistance. Accordingly, it is most often observed in alcoholics, obese persons, and diabetic patients. It is also frequently caused by drugs,83 viral hepatitis,84 chemical intoxication,85 pregnancy,86 intestinal bypass surgery,87 and malnutrition.88 Histological findings reveal that fat deposits in the liver may vary in size and distribution. Hepatocytes may contain large fat droplets with an anomalously displaced nucleus (macrovesicular type) or multiple small droplets with a central nucleus (microvesicular type). Macrovesicular type steatosis is typically seen in metabolic syndrome, while the microvesicular type is observed in acute fatty liver during pregnancy, chemical intoxication, and Rey's syndrome. In acute alcoholic hepatic steatosis, mixed macrovesicular and foamy-type fatty degeneration (cell swelling with a massive accumulation of microvesicular fat droplets) in the perivenular region occurs.89 Most fatty liver patients are asymptomatic. However, an enflamed fatty liver may lead to cirrhosis and finally hepatocellular carcinoma.
A fatty liver that was caused by excessive alcohol intake may result in liver inflammation (alcoholic hepatitis) and scarring (alcoholic cirrhosis), causing alcoholic liver disease. The development of an enflamed fatty liver in the absence of pregnancy and alcoholism is referred to as nonalcoholic steatohepatitis (NASH). The term nonalcoholic fatty liver disease (NAFLD) refers to fatty liver, NASH, and cirrhosis. Although NASH may occur in all ages and both genders, it is commonly found in middle-aged (40-60 year-old) women, many of whom are obese, or may have type 2 diabetes mellitus (insulin resistance) or hyperlipidemia.90 People who are neither overweight nor have diabetes mellitus or hyperlipidemia have been recently reported as suffering from NASH.91
NASH develops for various reasons, and proceeds by several poorly understood biochemical mechanisms. The causes of steatosis may involve the reduced synthesis of very low density lipoprotein (VLDL) and elevated levels of hepatic triacylglycerols, because of the reduced levels of fatty acid oxidation or an increase in the amount of lipids that circulate to the liver. As lipids accumulate, lipid peroxidation is likely to occur in the presence of free radicals, causing cell damage, which results in inflammation. These changes will activate HSCs, causing fibrosis, cirrhosis, and portal hypertension, if NASH is advanced, up to 40% of NASH patients develop liver fibrosis or 5-10% cirrhosis.92
Hepatic steatosis is diagnosed nowadays by noninvasive imaging tests, such as ultrasonographic examination, CT, and MRI. The abnormality that can be detected in the laboratory is usually an increased aminotransferase level. For fatty liver associated with obesity, SGPT commonly exceeds SGOT, while SGPT is smaller than SGOT in alcoholic liver disease.93 In addition, serum alkaline phosphatase and y -glutamyl transpeptidase (GGT) are elevated in alcoholic liver disease and are within normal ranges in obesity-related hepatic steatosis.
No known treatment exists for fatty liver. The widely accepted treatment goal is to eliminate the potential causes and risk factors, since fatty liver due to obesity or alcoholism is reversible. Such actions as the discontinuation of drugs or toxins, body weight control and the prescription of hyperlipidemia and hyperglycemia help to reach this goal. Many other treatments have also been tested, including ursodeoxycholic acid (UDCA),94 metformin,95 rosiglitazone,96 betaine,97 and vitamins E and C.98 Although more investigations are required before recommendations can be made for NAFLD patients, UDCA and metformin seem promising. UDCA is a non-toxic natural bile acid that is initially used to dissolve gallstone and is now used to reduce liver fat deposition. Metformin, an antidiabetic drug and an insulin-sensitizing agent, is potentially useful for the fatty liver caused by insulin resistance and hyperisulinemia.95
A recent study indicated that patients with fatty liver disease should be encouraged to take vitamin E and C supplements.98 This treatment was claimed to be safe and affordable. Patients were randomly prescribed either oral vitamin E (600 IU/day) plus vitamin C (500 mg/day) or ursodeoxycholic acid (10 mg/kg/day). Clinical data suggested that at the end of 6 months of therapy, vitamin E plus C combination treatment yielded results that were comparable to those obtained with ursodeoxycholic acid. Serum alanine aminotransferase levels declined to normal levels in 17 of the 27 (63%) patients who received vitamin E plus C, and 16 of the 29 (55%) patients who received ursodeoxycholic acid. Antioxidants such as vitamin E and C appear to have a beneficial effect on fatty liver. In this regard, Spirulina seems to be a candidate for the attenuation of fatty liver.
Regulation of Lipid Metabolism and Oxidative Stress by Spirulina on Fatty Liver
As reported elsewhere, Spirulina prevents the formation of fatty liver in animal models99-105 and in humans.106-109 The effectiveness of Spirulina against fatty liver may follow from its antioxidants, which include GLA, selenium, phycobilins, vitamins and carotenoids (j3-carotene). In addition, essential fatty acids like GLA can prevent the accumulation of cholesterol in the body.109
In an animal model, fatty liver has been reported to be induced by a high cholesterol diet,100 a 60% fructose diet,101 carbon tetrachloride,102,103 and alloxan-induced experimental diabetes.105 The high fructose diet induces fatty liver because the rapid conversion of fructose to acyl-CoA or a-glycerophosphoric acid elevates plasma lipid level.110 Fructose has been reported to have less effect on lipoprotein lipase (LPL) activation111 and to promote the activities of fatty acid synthesis-related enzymes such as acetyl-CoA carboxylase,112,113 fatty acid synthetase,112-114 and malic enzyme.112 The effectiveness of administering Spirulina to an animal with high fructose diet-induced hyperlipidemia (probably fatty liver) appears to be demonstrated in hypolipidemic effect,115,116 reduced liver triacylglycerol, and hypocholesterolemia.101 The beneficial effect of Spirulina may derive from the activated LPL activities, which are determined using postheparin serum.116
Carbon tetrachloride-induced hepatocyte injury and fatty liver have been suggested to be caused by an increase in the synthesis of liver fatty acids, elevated lipoperoxidation and altered release of hepatic lipoprotein.102-119 The prevention by S. maxima of carbon tetrachloride-induced fatty liver is evidenced by restored lipoprotein levels and hypocholesterolemic, and hypotriacylglycerolemic effects.102-103 It has a similar protective effect on a high fructose101,115 and hypercholesterolemic diet-induced120 fatty liver. In an animal study of fatty liver induced by the administering of simvastatin (75 mg/kg body weight), ethanol (20%) and a hypercholesterolemic diet (1% cholesterol) to male CD-1 mice for 5 days, significant measured liver total lipids (40%), liver triacylglycerols (50%), serum high-density lipoprotein (HDL) (45%), and serum triacylglycerols (50%) all markedly decreased when animals received Spirulina treatment (10% of diet) 2 weeks prior to the onset of the fatty liver.120
Different extracts of Spirulina (5% of diet composition) were investigated to determine the preventative effects on hypercholesterolemia and hypertriacylglycerolemia.103,121 Oil extracts and defatted extracts were fed to male rats before a single intraperitoneal injection of carbon tetrachloride. The total liver lipids differed significantly, by 28% between the group that had not (50 mg/g wet weight) and the group that had (36.2 mg/g wet weight) been given Spirulina defatted-extracts. It differed by 30% between the former group and the group that had been treated with an oil fraction. Liver total triacylglycerols (defatted: 80%; oil: 54%) and cholesterol (defatted: 74.5%; oil: 71%) were similarly reduced. Liver total lipid, triacylglycerol, and cholesterol levels fell to normal ranges following the treatment.102,103 However, hypotriacylglycerolemic and hypocholesterolemic effects in serum vary among studies, because of variations among the fractions of Spirulina, the dosage effect, the causes of fatty liver, gender, and the experimental schedule.101-103,105,116 The hypoglycemic action of S. maxima in rats has been examined using a water-soluble fraction.121 A study was conducted to measure the effect of S. maxima on serum glucose levels in diabetic rats. It was suggested that the water-soluble fraction suppressed serum glucose levels at fasting, while the water-insoluble fraction was found to be effective in reducing glucose levels at glucose loading.121
Studies have reported that the relief of accumulated liver lipids in a Spirulina-treated animal model is probably caused by increasing LPL activity,116 increasing the level of serum HDL and restoring LDL and VLDL levels.103,105 Moreover, the reduced hepatic lipoperoxidation contributes to the attenuation of the carbon tetrachloride-induced fatty liver.103,105 Spirulina treatment caused liver microsomal TBARS, a lipoperoxidation product, to drop to a normal level,103,122 probably because of the antioxidant constituents, such as selenium, chlorophyll, carotene, y-linolenic acid, vitamins E and C, and phycocyanins.13,123
The fatty liver is also commonly associated with Type II diabetes, which is related to the variation in insulin resistance and hyperinsulinemia. One study indicated that the dietary administering of 5% S. maxima (SM) dried powder for 4 weeks to alloxan-induced (250 mg/kg body weight, intraperitoneal) diabetes in CD-1 mice prevented the formation of fatty liver in male and female animals.105 The glucose, cholesterol, triacylglycerol, total lipid, and TBARS levels in the serum and the liver were measured. Serum lipoprotein, HDL-cholesterol and LDL plus VLDL levels were also determined. The hypoglycemia effect was seen in Spirulina-treated diabetic male mice but not in female mice. No significant change in serum and liver cholesterol levels was observed among the animals that received SM. The major effect by which Spirulina reduces the level of fat in the liver is by reducing triacylglycerol levels in the serum and the liver. Having received SM, female mice exhibited reduced liver triacylglycerol and a significant decline (p < .05) in serum triacylglycerol. Male mice, however, exhibited a significant decrease (p < .05) in the triacylglycerol level in the liver rather than in the serum. Reduced triacylglycerol accumulation relieves the formation of fatty liver. The hypotriacylglycerolemic effect of Spirulina may help to reduce liver total lipid and thereby lower the risk of hepatic steatosis.
Gonadectomized female animals reportedly are more likely to develop diabetes because of the effect of female sex steroids on glucose metabolism.124 However, female CD-1 mice were more resistant to alloxan-induced diabetes, but more responsive to the beneficial effects of S. maxima, such as the hypotriglycerolemic effect, reduced liver lipids, lowered liver microsomal TBARS levels, and elevated HDL.105 The benefit of Spirulina is also evident in the appearance of liver lobes. Round liver lobules were observed in mice with diabetes that had not undergone Spirulina treatment, while normal liver lobes were observed in treated diabetic mice.
The hypocholesterolemic effect of Spirulina in humans has been reported.107,125 Reduced serum cholesterol (4.5%), triacylglycerol and LDL were observed when Spirulina (4.2 g/day) was added for 8 weeks to the diet of thirty Japanese males with high cholesterol, mild hypertension, and hyperlipidemia. Serum cholesterol returned to its initial level if the intake of Spirulina was discontinued after 4 weeks. In addition, the hypocholesterolemic effect was greater in men with a higher cholesterol diet.125 Becker et al. (1986)107 evaluated clinical and biochemical outcomes following the application of Spirulina to treat obesity. They found weight loss accompanied by reduced cholesterol level.
Similar lipid lowering effects were observed on long-term studies of Spirulina supplementation in patients with hyperlipidemic nephrotic syndrome109 and type 2 diabetes mellitus.108,126 Spirulina improved long-term regulation of blood sugar in nephrotic and NIDDM patients. In the study, 23 patients (age 2-13 years) with hyperlipidemic nephrotic syndrome received medication plus Spirulina supplementation (1 g/day) for 2 months markedly reduced serum total cholesterol (TC). Other beneficial effects included increased ratio of HDL-cholesterol (HDL-C):LDL-C and decreased ratio of LDL-C:HDL-C and TC:HDL-C. Samuel (2002)109 concluded that the lipid-lowering effects in patients with hyperlipidemic nephrotic syndrome were due to the large amount of GLA contained in Spirulina. GLA, an essential omega-6 fatty acid and a potential precursor of arachidonic acid (AA), has been proven to prevent fatty liver induced by ethanol, carbon tetrachloride, and omega-6 fatty acid deficiency127,128 through up-regulated PGE2 production.129,130 PGE2 and its precursor, arachidonic acid, have been reported to be associated with lipoprotein and triacylglycerol secretion by liver.127 In addition, in the NIDDM study carried out by Parikh (2001),108 lipid lowering effects of Spirulina were demonstrated in the reduced content of triacylglycerols and LDL-C, and the lowered indices of TC:HDL-C and LDL-C:HDL-C as observed in nephrotic patients. Besides, elevated level of HDL-C and apolipoprotein ratio of A1:B was also observed.
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