Abstract
Recent nutritional epidemiological surveys showed that serum β-cryptoxanthin inversely associates with the risks for insulin resistance and liver dysfunction. Consumption of β-cryptoxanthin possibly prevents nonalcoholic steatohepatitis (NASH), which is suggested to be caused by insulin resistance and oxidative stress from nonalcoholic fatty liver disease. To evaluate the effect of β-cryptoxanthin on diet-induced NASH, we fed a high-cholesterol and high-fat diet (CL diet) with or without 0.003% β-cryptoxanthin to C56BL/6J mice for 12 weeks. After feeding, β-cryptoxanthin attenuated fat accumulation, increases in Kupffer and activated stellate cells, and fibrosis in CL diet-induced NASH in the mice. Comprehensive gene expression analysis showed that although β-cryptoxanthin histochemically reduced steatosis, it was more effective in inhibiting inflammatory gene expression change in NASH. β-Cryptoxanthin reduced the alteration of expression of genes associated with cell death, inflammatory responses, infiltration and activation of macrophages and other leukocytes, quantity of T cells, and free radical scavenging. However, it showed little effect on the expression of genes related to cholesterol and other lipid metabolism. The expression of markers of M1 and M2 macrophages, T helper cells, and cytotoxic T cells was significantly induced in NASH and reduced by β-cryptoxanthin. β-Cryptoxanthin suppressed the expression of lipopolysaccharide (LPS)-inducible and/or TNFα-inducible genes in NASH. Increased levels of the oxidative stress marker thiobarbituric acid reactive substances (TBARS) were reduced by β-cryptoxanthin in NASH. Thus, β-cryptoxanthin suppresses inflammation and the resulting fibrosis probably by primarily suppressing the increase and activation of macrophages and other immune cells. Reducing oxidative stress is likely to be a major mechanism of inflammation and injury suppression in the livers of mice with NASH.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent forms of chronic liver disease in the developed countries and is frequently associated with obesity, metabolic syndrome, and type 2 diabetes
Calculation of the F4/80-positive area is shown in Figure 2. b-Cryptoxanthin suppressed the accumulation of lipid droplets, collagen deposition, and F4/80-positive macrophages, which causes inflammation, in the livers of mice fed the cholesterol and high-fat diet (CL diet)
We previously reported that bcryptoxanthin was highly accumulated in the liver of rats fed a diet containing the Satsuma mandarin extract for 8 weeks [39]. bCryptoxanthin probably accumulated in the liver and directly reduced the increased level of the oxidative stress marker thiobarbituric acid reactive substances (TBARS) in Nonalcoholic steatohepatitis (NASH)
Summary
Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent forms of chronic liver disease in the developed countries and is frequently associated with obesity, metabolic syndrome, and type 2 diabetes. Nonalcoholic steatohepatitis (NASH), an advanced form of NAFLD, is characterized by hepatocellular steatosis along with lobular inflammation and fibrosis and may lead to liver cirrhosis and hepatocellular carcinoma [1]. Insulin resistance, increased oxidative stress and subsequent lipid peroxidation, and increased proinflammatory cytokine release are believed to be the major causes of progression to NASH, the mechanisms have not been fully elucidated [1,2]. No prevention or treatment of NASH has been fully established. Dietary modification and gradual weight loss are current mainstays of NASH treatment.
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