β-Cryptoxanthin Alleviates Diet-Induced Nonalcoholic Steatohepatitis by Suppressing Inflammatory Gene Expression in Mice

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.

β‐Cryptoxanthin exerts greater cardioprotective effects on cardiac ischemia‐reperfusion injury than astaxanthin by attenuating mitochondrial dysfunction in mice

“…However, although previous studies demonstrated the beneficial effect of low dosage of astaxanthin and vitamin E (25-75 mg/kg) on oxidative stress [5,18,39,40], the variation of the dosage to balance the oxidative stress and exhibit the beneficial effect still unclear. Meta-analysis of the effect of the dosage on mortality by Abner et al found that a moderate dosage of vitamin E (cut-point of 400 IU/day or 330 mg/kg) did not affect the risk of all-cause mortality [41], whereas Miller et al found a significantly increased risk of mortality for doses above 400 IU [42].…”

“…However, although previous studies demonstrated the beneficial effect of low dosage of astaxanthin and vitamin E (25–75 mg/kg) on oxidative stress , the variation of the dosage to balance the oxidative stress and exhibit the beneficial effect still unclear. Meta‐analysis of the effect of the dosage on mortality by Abner et al.…”

Correlation of plasma metabolites with glucose and lipid fluxes in human insulin resistance

“…In total, 60 participants were included with obesity (BMI ≥ 30 kg m −2 ), of which 30 male and 30 female, aged 51 ± 12 (mean ± SD) years with a BMI of 39 [34][35][36][37][38][39][40][41][42][43][44]…”

Hepatic Transcriptome Profiles of Mice with Diet-Induced Nonalcoholic Steatohepatitis Treated with Astaxanthin and Vitamin E

“…We have previously reported that another xanthophyll carotenoid, β-cryptoxanthin, which is found particularly in Satsuma mandarin oranges ( Citrus unshiu Marc. ), attenuated fat accumulation, inflammation, and fibrosis in mice with CL diet-induced NASH [15]. Comprehensive gene expression analysis showed that β-cryptoxanthin effectively suppressed the expression of inflammatory genes but not the expression of the genes associated with steatosis [15].…”

“…), attenuated fat accumulation, inflammation, and fibrosis in mice with CL diet-induced NASH [15]. Comprehensive gene expression analysis showed that β-cryptoxanthin effectively suppressed the expression of inflammatory genes but not the expression of the genes associated with steatosis [15]. The study suggested that β-cryptoxanthin suppressed inflammation and the resulting fibrosis primarily by suppressing the increase and activation of macrophages and other immune cells [15].…”