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

PLoS One. 2014 Jun 5;9(6):e97841. doi: 10.1371/journal.pone.0097841. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / etiology*
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Biomarkers / blood
  • Biomarkers / metabolism
  • Cholesterol / adverse effects*
  • Cholesterol / blood
  • Cholesterol / metabolism
  • Disease Models, Animal
  • Gene Expression
  • Inflammation / blood
  • Inflammation / complications*
  • Inflammation / metabolism
  • Inflammation Mediators / blood
  • Inflammation Mediators / metabolism
  • Male
  • Non-alcoholic Fatty Liver Disease / etiology*
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology
  • RNA, Messenger / genetics
  • Rabbits
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism

Substances

  • Biomarkers
  • Inflammation Mediators
  • RNA, Messenger
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Cholesterol

Grant support

This study was partly supported by the Korea Institute of Science and Technology Institutional Program (Project No. 2E24080); a grant from the Korean Health Technology R&D Project of the Ministry for Health, Welfare & Family Affairs of the Republic of Korea (A070001); and a grant from the Korea University-Korea Institute of Science and Technology Graduate School Converging Science and Technology(R1307921). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.