Endocrine Pharmacology
Histidine and carnosine alleviated hepatic steatosis in mice consumed high saturated fat diet

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Abstract

The effects of histidine, alanine and carnosine on activity and/or mRNA expression of lipogenic enzymes and sterol regulatory element-binding proteins (SREBPs) in liver and adipose tissue from high fat diet treated mice were examined. Histidine, alanine or carnosine, each agent at 1 g/l was added into drinking water for 8-wk supplement. Histidine or carnosine supplement increased hepatic levels of alanine, histidine and carnosine. High fat diet evoked lipogenesis via raising the activity and mRNA expression of glucose-6-phosphate dehydrogenase, malic enzyme, fatty acid synthase (FAS), 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, SREBP-1a, -1c and -2 in liver and adipose tissue (P < 0.05), which consequently increased mice body weight, epididymal fat, and hepatic triglyceride and cholesterol contents (P < 0.05). The intake of histidine or carnosine significantly diminished the activity and mRNA expression of malic enzyme, FAS, HMG-CoA reductase, SREBP-1c and SREBP-2, which led to lower body weight, epididymal fat, and hepatic triglyceride and cholesterol levels (P < 0.05). Mice consumed high fat diet exhibited hyper-insulinemia, hyper-leptinemia, hypo-adiponectinemia and hypo-ghrelinemia. Histidine or carnosine treatments significantly improved insulin sensitivity and attenuated hyper-insulinemia (P < 0.05). These results support that histidine and carnosine are effective agents for mitigating high fat diet induced hepatic steatosis.

Introduction

Hepatic steatosis, hyperlipidemia and obesity due to lipid accumulation are risk factors associated with the prevalence of cardiovascular diseases and metabolic disorders (Daskalopoulou et al., 2004, Franks et al., 2010). Enhanced lipogenesis is a major contributor toward lipid accumulation. Thus, any agent with anti-lipogenic effect may improve lipid metabolism disorders, and alleviate steatosis and obesity.

Carnosine (beta-alanyl-l-histidne) is a dipeptide synthesized from the precursors l-histidine and β-alanine by carnosine synthetase, and present in brain, skeletal muscle and liver (Boldyrev and Severin, 1990). Several in vivo studies have reported that carnosine, histidine or alanine could provide anti-oxidative, anti-inflammatory and anti-glycative protection, and support that they are potent nutraceutical agents (Shimizu, 2004, Liu et al., 2008, Hipkiss, 2009). Our previous study observed that histidine or carnosine treatments dose-dependently reduced hepatic triglyceride and cholesterol contents under diabetic condition, and suggested that these compounds might possess anti-lipogenic activity (Lee et al., 2005). Hence, a further study was designed to explore whether these agents were able to attenuate lipogenesis in liver and adipose tissue, especially when high fat diet was supplied.

Malic enzyme, fatty acid synthase (FAS) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase are lipogenic enzymes, and involved in the biosynthesis of triglyceride and cholesterol in liver and adipose tissue. Sterol regulatory element-binding proteins (SREBPs) are important transcription factors responsible for fatty acid and cholesterol metabolism (Shimano et al., 1999), in which SREBP-1c is more effective in modulating the expression of genes involved in fatty acid synthesis, whereas SREBP-2 is more predominant in mediating genes associated with cholesterol synthesis (Shimomura et al., 1997, Horton et al., 1998). If carnosine, histidine or alanine could down-regulate these lipogenic enzymes and SREPBs, they may decline lipogenesis and reduce triglyceride and cholesterol levels in tissues. In addition, hormones such as insulin, leptin and adiponectin also affect lipid metabolism. It is reported that food and food components such as fish oil, tea polyphenols and chlorogenic acid could improve obesity and metabolic disorders via regulating these hormones (Bose et al., 2008, Saraswathi et al., 2009, Cho et al., 2010). If carnosine, histidine or alanine could mediate these hormones, they may regulate lipid metabolism through endocrinal pathways.

The major purpose of this study was to investigate the effects of histidine, alanine and carnosine on activity and/or mRNA expression of lipogenic enzymes and SREBPs in liver and adipose tissue from high fat diet treated mice. The influence of these compounds upon the variation of insulin, leptin, adiponectin and ghrelin in circulation was also evaluated.

Section snippets

Animals and diets

Male 3-week-old C57BL/6 mice were obtained from National Laboratory Animal Center (National Science Council, Taipei City, Taiwan). Mice were housed on a 12-h light-12-h dark schedule, and fed with water and mouse standard diet for one week acclimation. Mice were then divided into two groups, one continuously consumed control diet, and the other was switched to a high fat diet containing 60% calories as fat (Research Diet D12492; Research Diets, New Brunswick, NJ, USA), in which saturated fat

Results

Mice consumed high fat diet had significantly higher final body weight, liver weight, epididymal white adipose tissue, water intake and feed intake (Table 1, P < 0.05); however, histidine or carnosine treatments significantly lowered mice final body weight, liver weight and epididymal white adipose tissue (P < 0.05). As shown in Table 2, the supplement of three test agents significantly increased the hepatic concentrations of these compounds in mice with control diet (P < 0.05). High fat diet alone

Discussion

The high fat diet we used for present study contained 55% saturated fat, which contributed to 33% of total energy. This high saturated fat diet effectively enhanced the activity and/or mRNA expression of four enzymes and three SREBPs responsible for triglyceride and cholesterol biosynthesis, which clearly explained the observed elevated lipogenesis in liver and epididymal white adipose tissue. Our present study further found that the intake of histidine or carnosine increased their levels in

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgement

This study was supported by a grant from China Medical University, Taichung City, Taiwan, ROC (Grant CMU99-asia-01).

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