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Cholesterol-induced non-alcoholic fatty liver disease and atherosclerosis aggravated by systemic inflammation.

ABSTRACT: Although triglyceride accumulation in the liver causes non-alcoholic fatty liver disease (NAFLD), hypercholesterolemia is also a main cause of NAFLD as well as atherosclerosis. However, NAFLD and atherosclerosis have not been investigated simultaneously in animal models fed a high-cholesterol diet. Moreover, it is unclear whether systemic inflammation can exacerbate both pathologies in the same model. Accordingly, this study investigated the effect of additional systemic inflammation on NAFLD and atherosclerosis induced by cholesterol overload in wild animals. New Zealand white rabbits were divided into 4 groups: groups I (control) and II received normal chow, and groups III and IV received a 1% cholesterol diet. To induce inflammation via toll-like receptor (TLR)-4 signaling, groups II and IV received subcutaneous injections of 0.5 mL of 1% carrageenan every 3 weeks. After 3 months, total cholesterol markedly increased in groups III and IV, and the serum expressions of systemic inflammatory markers were elevated in the groups II-IV. Early NAFLD lesions (e.g., mild fatty changes in the liver with sporadic fibrosis) and atherosclerosis (e.g., intimal hyperplasia composed of foam cells) were observed in both the liver and aorta specimens from group III, and advanced lesions were observed in group IV. The expressions of inflammatory cellular receptors, TLR-2 and TLR-4, in the aorta gradually increased from group I to IV but were similar in the liver in groups II-IV. Cholesteryl ester (CE) levels were higher in group IV than in group III, although the difference was not significant. CE levels in the aorta were similar between groups III and IV. Systemic inflammation can simultaneously exacerbate existing early lesions due to cholesterol overload in both the liver and aorta of rabbits. However, the cellular response of inflammatory receptors and expression of cholesterol metabolites differ between these organs.

SUBMITTER: Kim EJ

PROVIDER: S-EPMC4046981 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background & aimsRemnant lipoprotein cholesterol (RLP-C) is an atherogenic lipid profile associated with non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). With increased rates of CVD seen in adults with NAFLD, RLP-C has the potential to identify individuals with NAFLD who are at increased risk of CVD. This study examined in adolescents sex-different associations among RLP-C, NAFLD, and cardiometabolic risk factors, and whether RLP-C is associated with NAFLD beyond traditional cardiometabolic risk factors.MethodsAdolescents in the Raine Study had anthropometry, clinical, biochemistry and arterial stiffness measurements recorded at 17 years of age. Fatty liver, subcutaneous and visceral adipose thickness were assessed using abdominal ultrasound. Relationships among RLP-C, NAFLD, liver biochemistry, insulin resistance, adipokines, adiposity and arterial stiffness were assessed.ResultsNAFLD was diagnosed in 15.1% (19.6% females and 10.7% males) of adolescents. Increasing RLP-C levels were associated with increasing severity of hepatic steatosis and metabolic syndrome. Adolescents with NAFLD and serum RLP-C levels in the highest quartile compared with the lowest quartile, had higher serum leptin, homeostatic model assessment of insulin resistance (HOMA-IR), high-sensitivity C-reactive protein, low-density-lipoprotein cholesterol, triglycerides, BMI, subcutaneous and visceral adipose thickness, systolic blood pressure and arterial stiffness, but lower adiponectin and high-density-lipoprotein cholesterol. Using multivariable logistic regression, RLP-C in the lowest quartile compared with the highest quartile was associated with 85% lower odds of NAFLD in males and 55% in females, after adjusting for waist circumference, leptin, ALT, adiponectin and HOMA-IR.ConclusionsThere is an association between RLP-C and NAFLD beyond traditional risk factors of adiposity and insulin resistance in adolescents. Although raised serum RLP-C levels were associated with the severity of hepatic steatosis and markers of cardiometabolic risk, lower serum RLP-C might reflect reduced cardiovascular risk.Lay summaryRemnant lipoprotein cholesterol (RLP-C) is a part of the blood cholesterol that is linked with heart disease and non-alcoholic fatty liver disease (NAFLD) in adults. In the Raine Study, teenagers with high RLP-C levels had more severe fat accumulation in their liver. Thus, RLP-C might be the hidden link between NAFLD and future risk of heart disease.

Project description:IntroductionNon-alcoholic fatty liver disease (NAFLD) is characterized by excess accumulation of triglycerides within the liver. However, whether the circulating levels of triglycerides and cholesterol transported in triglyceride-rich lipoproteins (remnant cholesterol, remnant-C) are related to the occurrence of NAFLD has not yet been studied. This study aims to assess the association of triglycerides and remnant-C with NAFLD in a Chinese cohort of middle aged and elderly individuals.MethodsAll subjects in the current study are from the 13,876 individuals who recruited in the Shandong cohort of the REACTION study. We included 6,634 participants who had more than one visit during the study period with an average follow-up time of 43.34 months. The association between lipid concentrations and incident NAFLD were evaluated by unadjusted and adjusted Cox proportional hazard models. The potential confounders were adjusted in the models including age, sex, hip circumference (HC), body mass index (BMI), systolic blood pressure, diastolic blood pressure, fasting plasma glucose (FPG), diabetes status and cardiovascular disease (CVD) status.ResultsIn multivariable-adjusted Cox proportional hazard model analyses, triglycerides (hazard ratio[HR], 95% confidence interval [CI]:1.080,1.047-1.113;p<0.001), high-density lipoprotein cholesterol (HDL-C) (HR, 95% CI: 0.571,0.487-0.670; p<0.001), and remnant-C (HR, 95% CI: 1.143,1.052-1.242; p=0.002), but not total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C), were associated with incident NAFLD. Atherogenic dyslipidemia (triglycerides>1.69 mmol/L, HDL-C<1.03 mmol/L in men or<1.29 mmol/L in women) was also associated with NAFLD (HR, 95% CI: 1.343,1.177-1.533; p<0.001). Remnant-C levels were higher in females than in males and increased with increasing BMI and in participants with diabetes and CVD compared with those without diabetes or CVD. After adjusting for other factors in the Cox regression models, we found that serum levels of TG and remnant-C, but not TC or LDL-C, were associated with NAFLD outcomes in women group, non-cardiovascular disease status, non-diabetes status and middle BMI categories (24 to 28 kg/m2).DiscussionIn the middle aged and elderly subset of the Chinese population, especially those who were women, non-CVD status, non-diabetes status and middle BMI status (24 to 28 kg/m2), levels of triglycerides and remnant-C, but not TC or LDL-C, were associated with NAFLD outcomes independent of other risk factors.

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Cholesterol-induced non-alcoholic fatty liver disease and atherosclerosis aggravated by systemic inflammation.

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