cryptoxanthins and Insulin-Resistance

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver disorders worldwide. It is associated with clinical states such as obesity, insulin resistance, and type 2 diabetes, and covers a wide range of liver changes, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. Metabolic disorders, such as lipid accumulation, insulin resistance, and inflammation, have been implicated in the pathogenesis of NAFLD, but the underlying mechanisms, including those that drive disease progression, are not fully understood. Both innate and recruited immune cells mediate the development of insulin resistance and NASH. Therefore, modifying the polarization of resident and recruited macrophage/Kupffer cells is expected to lead to new therapeutic strategies in NAFLD. Oxidative stress is also pivotal for the progression of NASH, which has generated interest in carotenoids as potent micronutrient antioxidants in the treatment of NAFLD. In addition to their antioxidative function, carotenoids regulate macrophage/Kupffer cell polarization and thereby prevent NASH progression. In this review, we summarize the molecular mechanisms involved in the pathogenesis of NAFLD, including macrophage/Kupffer cell polarization, and disturbed hepatic function in NAFLD. We also discuss dietary antioxidants, such as β-cryptoxanthin and astaxanthin, that may be effective in the prevention or treatment of NAFLD.

Topics: Antioxidants; Carotenoids; Cryptoxanthins; Humans; Insulin Resistance; Liver; Macrophages; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Xanthophylls

There are concerns that weight-loss (WL) diets based on very low carbohydrate (LC) intake have a negative impact on antioxidant status and biomarkers of cardiovascular and metabolic health. Obese men (n 16) participated in a randomised, cross-over design diet trial, with food provided daily, at approximately 8.3 MJ/d (approximately 70 % of energy maintenance requirements). They were provided with two high-protein diets (30 % of energy), each for a 4-week period, involving a LC (4 % carbohydrate) and a moderate carbohydrate (MC, 35 % carbohydrate) content. Body weight was measured daily, and weekly blood samples were collected. On average, subjects lost 6.75 and 4.32 kg of weight on the LC and MC diets, respectively (P < 0.001, SED 0.350). Although the LC and MC diets were associated with a small reduction in plasma concentrations of retinol, vitamin E (α-tocopherol) and β-cryptoxanthin (P < 0.005), these were still above the values indicative of deficiency. Interestingly, plasma vitamin C concentrations increased on consumption of the LC diet (P < 0.05). Plasma markers of insulin resistance (P < 0.001), lipaemia and inflammation (P < 0.05, TNF-α and IL-10) improved similarly on both diets. There was no change in other cardiovascular markers with WL. The present data suggest that a LC WL diet does not impair plasma indices of cardiometabolic health, at least within 4 weeks, in otherwise healthy obese subjects. In general, improvements in metabolic health associated with WL were similar between the LC and MC diets. Antioxidant supplements may be warranted if LC WL diets are consumed for a prolonged period.

Topics: Adult; Aged; alpha-Tocopherol; Antioxidants; Ascorbic Acid; Biomarkers; Cardiovascular Diseases; Cross-Over Studies; Cryptoxanthins; Diet, Carbohydrate-Restricted; Diet, Reducing; Dietary Carbohydrates; Dietary Proteins; Endothelium, Vascular; Energy Intake; Humans; Hyperlipidemias; Inflammation Mediators; Insulin Resistance; Male; Metabolic Diseases; Middle Aged; Nutritional Requirements; Obesity; Risk Factors; Vitamin A; Weight Loss; Xanthophylls

High concentrations of carotenoids are protective against cardiometabolic risk traits (CMTs) in adults and children. We recently showed in non-diabetic Mexican American (MA) children that serum α-carotene and β-carotene are inversely correlated with obesity measures and triglycerides and positively with HDL cholesterol and that they were under strong genetic influences. Additionally, we previously described a Pediatric Metabolic Index (PMI) that helps in the identification of children who are at risk for cardiometabolic diseases. Here, we quantified serum lycopene and β-cryptoxanthin concentrations in approximately 580 children from MA families using an ultraperformance liquid chromatography-photodiode array and determined their heritabilities and correlations with CMTs. Using response surface methodology (RSM), we determined two-way interactions of carotenoids and PMI on Matsuda insulin sensitivity index (ISI). The concentrations of lycopene and β-cryptoxanthin were highly heritable [h

Topics: Adolescent; Beta-Cryptoxanthin; Body Mass Index; Carotenoids; Child; Cholesterol, HDL; Chromatography, Liquid; Diabetes Mellitus, Type 2; Diet; Female; Humans; Insulin Resistance; Lycopene; Male; Mexican Americans; Obesity; Phenotype; Risk Factors; Texas; Triglycerides; Waist Circumference

The aim of this experiment was to determine the effects of β-cryptoxanthin (BCX) on the cardiometabolic health risk factors and NF-κB and Nrf2 pathway in insulin resistance induced by high-fat diet (HFD) in rodents. Twenty-eight Sprague-Dawley rats were allocated into four groups: (1) Control, rats fed a standard diet for 12 weeks; (2) BCX, rats fed a standard diet and supplemented with BCX (2.5 mg/kg BW) for 12 weeks; (3) HFD, rats fed a HFD for 12 weeks, (4) HFD + BCX, rats fed a HFD and supplemented with BCX for 12 weeks. BCX reduced cardio-metabolic health markers and decreased inflammatory markers (P < 0.001). Rats fed a HFD had the lower total antioxidant capacity and antioxidant enzymes activities and higher MDA concentration than control rats (P < 0.001 for all). Comparing with the HFD group, BCX in combination with HFD inhibited liver NF-κB and TNF-α expression by 22% and 14% and enhanced liver Nrf2, HO-1, PPAR-α, and p-IRS-1 by 1.43, 1.41, 3.53, and 1.33 fold, respectively (P < 0.001). Furthermore, in adipose tissue, BCX up-regulated Nrf2, HO-1, PPAR-α, and p-IRS-1 expression, whereas, down-regulated NF-κB and TNF-α expression. In conclusion, BCX decreased visceral fat and cardiometabolic health risk factors through modulating expressions of nuclear transcription factors.

Topics: Adipose Tissue; Animals; Beta-Cryptoxanthin; Blood Glucose; Diet, High-Fat; Humans; Insulin; Insulin Resistance; Liver; Male; Malondialdehyde; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Rats; Rats, Sprague-Dawley

Excessive hepatic lipid accumulation promotes macrophages/Kupffer cells activation, resulting in exacerbation of insulin resistance and progression of nonalcoholic steatohepatitis (NASH). However, few promising treatment modalities target lipotoxicity-mediated hepatic activation/polarization of macrophages for NASH. Recent epidemiological surveys showed that serum β-cryptoxanthin, an antioxidant carotenoid, was inversely associated with the risks of insulin resistance and liver dysfunction. In the present study, we first showed that β-cryptoxanthin administration ameliorated hepatic steatosis in high-fat diet-induced obese mice. Next, we investigated the preventative and therapeutic effects of β-cryptoxanthin using a lipotoxic model of NASH: mice fed a high-cholesterol and high-fat (CL) diet. After 12 weeks of CL diet feeding, β-cryptoxanthin administration attenuated insulin resistance and excessive hepatic lipid accumulation and peroxidation, with increases in M1-type macrophages/Kupffer cells and activated stellate cells, and fibrosis in CL diet-induced NASH. Comprehensive gene expression analysis showed that β-cryptoxanthin down-regulated macrophage activation signal-related genes significantly without affecting most lipid metabolism-related genes in the liver. Importantly, flow cytometry analysis revealed that, on a CL diet, β-cryptoxanthin caused a predominance of M2 over M1 macrophage populations, in addition to reducing total hepatic macrophage and T-cell contents. In parallel, β-cryptoxanthin decreased lipopolysaccharide-induced M1 marker mRNA expression in peritoneal macrophages, whereas it augmented IL-4-induced M2 marker mRNA expression, in a dose-dependent manner. Moreover, β-cryptoxanthin reversed steatosis, inflammation, and fibrosis progression in preexisting NASH in mice. In conclusion, β-cryptoxanthin prevents and reverses insulin resistance and steatohepatitis, at least in part, through an M2-dominant shift in macrophages/Kupffer cells in a lipotoxic model of NASH.

Topics: Animals; Antioxidants; Cryptoxanthins; Dietary Fats; Glucose; Hepatic Stellate Cells; Homeostasis; Insulin Resistance; Kupffer Cells; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity

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.

Topics: Animals; Antigens, Differentiation; Cholesterol; Cryptoxanthins; Dietary Fats; Gene Expression Regulation; Inflammation; Insulin Resistance; Macrophages; Male; Mice; Non-alcoholic Fatty Liver Disease; T-Lymphocytes

Smoking is associated with low serum carotenoid concentrations. Prospective studies have found lower diabetes risk among persons with high-carotenoid diets. Whether diabetes risk is low in the rare smoker who has high serum carotenoid levels is unknown. The authors investigated the interaction of serum carotenoid concentrations and smoking with diabetes mellitus in 4,493 Black and White men and women aged 18-30 years in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The authors assessed 15-year (1985-2001) incident diabetes (148 cases), insulin concentration, and insulin resistance (homeostasis model assessment) in smokers and nonsmokers according to baseline levels of serum alpha-carotene, beta-carotene, zeaxanthin, beta-cryptoxanthin, and lycopene. Diabetes incidence was inversely associated with the sum of carotenoid concentrations in nonsmokers (per standard deviation (SD) increase, relative hazard = 0.74, 95% confidence interval: 0.55, 0.99) but not in current smokers (relative hazard = 1.13, 95% confidence interval: 0.83, 1.53) (p for interaction = 0.02). Similarly, year 15 insulin and insulin resistance values, adjusted for baseline levels, were inversely related to sum of carotenoids only in nonsmokers (per SD increase in insulin level, slope = -0.46 (p = 0.03); per SD increase in insulin resistance, slope = -0.14 (p = 0.01)). In CARDIA, higher serum carotenoid concentrations are associated with lower risk of diabetes and insulin resistance in nonsmokers but not in smokers.

Topics: Adolescent; Adult; beta Carotene; Black People; Carotenoids; Cryptoxanthins; Diabetes Mellitus; Female; Humans; Incidence; Insulin Resistance; Lycopene; Male; Proportional Hazards Models; Prospective Studies; Risk Factors; Smoking; White People; Xanthophylls; Zeaxanthins