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Aortic cholesterol accumulation correlates with systemic inflammation but not hepatic and gonadal adipose tissue inflammation in low-density lipoprotein receptor null mice.

ABSTRACT: Inflammation is a major contributor to the development of atherosclerotic plaque, yet the involvement of liver and visceral adipose tissue inflammatory status in atherosclerotic lesion development has yet to be fully elucidated. We hypothesized that an atherogenic diet would increase inflammatory response and lipid accumulation in the liver and gonadal adipose tissue (GAT) and would correlate with systemic inflammation and aortic lesion formation in low-density lipoprotein (LDL) receptor null (LDLr-/-) mice. For 32 weeks, LDLr-/- mice (n = 10/group) were fed either an atherogenic (high saturated fat and cholesterol) or control (low fat and cholesterol) diet. Hepatic and GAT lipid content and expression of inflammatory factors were measured using standard procedures. Compared with the control diet, the atherogenic diet significantly increased hepatic triglyceride and total cholesterol (TC), primarily esterified cholesterol, and GAT triglyceride content. These changes were accompanied by increased expression of acyl-CoA synthetase long-chain family member 5, CD36, ATP-binding cassette, subfamily A, member 1 and scavenger receptor B class 1, and they decreased the expression of cytochrome P450, family 7 and subfamily a, polypeptide 1 in GAT. Aortic TC content was positively associated with hepatic TC, triglyceride, and GAT triglyceride contents as well as plasma interleukin 6 and monocyte chemoattractant protein-1 concentrations. Although when compared with the control diet, the atherogenic diet increased hepatic tumor necrosis factor ? production, they were not associated with aortic TC content. These data suggest that the LDLr-/- mice responded to the atherogenic diet by increasing lipid accumulation in the liver and GAT, which may have increased inflammatory response. Aortic TC content was positively associated with systemic inflammation but not hepatic and GAT inflammatory status.

SUBMITTER: Wang S

PROVIDER: S-EPMC4001700 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Aortic cholesterol accumulation correlates with systemic inflammation but not hepatic and gonadal adipose tissue inflammation in low-density lipoprotein receptor null mice.

Wang Shu S Miller Bradley B Matthan Nirupa R NR Goktas Zeynep Z Wu Dayong D Reed Debra B DB Yin Xiangling X Grammas Paula P Moustaid-Moussa Naima N Shen Chwan-Li CL Lichtenstein Alice H AH

Nutrition research (New York, N.Y.) 20131201 12

Inflammation is a major contributor to the development of atherosclerotic plaque, yet the involvement of liver and visceral adipose tissue inflammatory status in atherosclerotic lesion development has yet to be fully elucidated. We hypothesized that an atherogenic diet would increase inflammatory response and lipid accumulation in the liver and gonadal adipose tissue (GAT) and would correlate with systemic inflammation and aortic lesion formation in low-density lipoprotein (LDL) receptor null (L ...[more]

PMID: 24267047

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Project description:BackgroundNon-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is characterised by dysfunctional lipid metabolism and cholesterol homeostasis, and a related chronic inflammatory response. NAFLD has become the most common cause of chronic liver disease in many countries, and its prevalence continues to rise in parallel with increasing rates of obesity. Here, we evaluated the putative NAFLD-attenuating effects of a multicomponent medicine consisting of 24 natural ingredients: Hepar compositum (HC-24).MethodsLdlr-/-.Leiden mice were fed a high-fat diet (HFD) with a macronutrient composition and cholesterol content comparable to human diets for 24 weeks to induce obesity-associated metabolic dysfunction, including hepatic steatosis and inflammation. HC-24 or vehicle control was administered intraperitoneally 3 times/week (1.5 ml/kg) for the last 18 weeks of the study. Histological analyses of liver and adipose tissue were combined with extensive hepatic transcriptomics analysis. Transcriptomics results were further substantiated with ELISA, immunohistochemical and liver lipid analyses.ResultsHFD feeding induced obesity and metabolic dysfunction including adipose tissue inflammation and increased gut permeability. In the liver, HFD-feeding resulted in a disturbance of cholesterol homeostasis and an associated inflammatory response. HC-24 did not affect body weight, metabolic risk factors, adipose tissue inflammation or gut permeability. While HC-24 did not alter total liver steatosis, there was a pronounced reduction in lobular inflammation in HC-24-treated animals, which was associated with modulation of genes and proteins involved in inflammation (e.g., neutrophil chemokine Cxcl1) and cholesterol homeostasis (i.e., predicted effect on 'cholesterol' as an upstream regulator, based on gene expression changes associated with cholesterol handling). These effects were confirmed by CXCL1 ELISA, immunohistochemical staining of neutrophils and biochemical analysis of hepatic free cholesterol content. Intrahepatic free cholesterol levels were found to correlate significantly with the number of inflammatory aggregates in the liver, thereby providing a potential rationale for the observed anti-inflammatory effects of HC-24.ConclusionsFree cholesterol accumulates in the liver of Ldlr-/-.Leiden mice under physiologically translational dietary conditions, and this is associated with the development of hepatic inflammation. The multicomponent medicine HC-24 reduces accumulation of free cholesterol and has molecular and cellular anti-inflammatory effects in the liver.

Project description:IMPORTANCE:Plasma low-density lipoprotein cholesterol (LDL-C) has been associated with aortic stenosis in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression. OBJECTIVE:To evaluate whether genetic data are consistent with an association between LDL-C, high-density lipoprotein cholesterol (HDL-C), or triglycerides (TG) and aortic valve disease. DESIGN, SETTING, AND PARTICIPANTS:Using a Mendelian randomization study design, we evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, constructed using single-nucleotide polymorphisms identified in genome-wide association studies for plasma lipids, were associated with aortic valve disease. We included community-based cohorts participating in the CHARGE consortium (n?=?6942), including the Framingham Heart Study (cohort inception to last follow-up: 1971-2013; n?=?1295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n?=?2527), Age Gene/Environment Study-Reykjavik (2000-2012; n?=?3120), and the Malmö Diet and Cancer Study (MDCS, 1991-2010; n?=?28,461). MAIN OUTCOMES AND MEASURES:Aortic valve calcium quantified by computed tomography in CHARGE and incident aortic stenosis in the MDCS. RESULTS:The prevalence of aortic valve calcium across the 3 CHARGE cohorts was 32% (n?=?2245). In the MDCS, over a median follow-up time of 16.1 years, aortic stenosis developed in 17 per 1000 participants (n?=?473) and aortic valve replacement for aortic stenosis occurred in 7 per 1000 (n?=?205). Plasma LDL-C, but not HDL-C or TG, was significantly associated with incident aortic stenosis (hazard ratio [HR] per mmol/L, 1.28; 95% CI, 1.04-1.57; P?=?.02; aortic stenosis incidence: 1.3% and 2.4% in lowest and highest LDL-C quartiles, respectively). The LDL-C GRS, but not HDL-C or TG GRS, was significantly associated with presence of aortic valve calcium in CHARGE (odds ratio [OR] per GRS increment, 1.38; 95% CI, 1.09-1.74; P?=?.007) and with incident aortic stenosis in MDCS (HR per GRS increment, 2.78; 95% CI, 1.22-6.37; P?=?.02; aortic stenosis incidence: 1.9% and 2.6% in lowest and highest GRS quartiles, respectively). In sensitivity analyses excluding variants weakly associated with HDL-C or TG, the LDL-C GRS remained associated with aortic valve calcium (P?=?.03) and aortic stenosis (P?=?.009). In instrumental variable analysis, LDL-C was associated with an increase in the risk of incident aortic stenosis (HR per mmol/L, 1.51; 95% CI, 1.07-2.14; P?=?.02). CONCLUSIONS AND RELEVANCE:Genetic predisposition to elevated LDL-C was associated with presence of aortic valve calcium and incidence of aortic stenosis, providing evidence supportive of a causal association between LDL-C and aortic valve disease. Whether earlier intervention to reduce LDL-C could prevent aortic valve disease merits further investigation.

Dataset Information

Aortic cholesterol accumulation correlates with systemic inflammation but not hepatic and gonadal adipose tissue inflammation in low-density lipoprotein receptor null mice.

Publications

Aortic cholesterol accumulation correlates with systemic inflammation but not hepatic and gonadal adipose tissue inflammation in low-density lipoprotein receptor null mice.

Similar Datasets

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