Inflammatory stress exacerbates lipid accumulation in hepatic cells and fatty livers of apolipoprotein E knockout mice

Hepatology. 2008 Sep;48(3):770-81. doi: 10.1002/hep.22423.


The prevailing theory in non-alcoholic fatty liver disease (NAFLD) is the "two-hit" hypothesis. The first hit mainly consists of lipid accumulation, and the second is subsequent systemic inflammation. The current study was undertaken to investigate whether inflammatory stress exacerbates lipid accumulation in liver and its underlying mechanisms. We used interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) stimulation in human hepatoblastoma cell line (HepG2) cells and primary hepatocytes in vitro, and casein injection in apolipoprotein E knockout mice in vivo to induce inflammatory stress. The effects of inflammatory stress on cholesterol accumulation were examined by histochemical staining and a quantitative intracellular cholesterol assay. The gene and protein expressions of molecules involved in cholesterol trafficking were examined by real-time polymerase chain reaction (PCR) and western blot. Cytokine production in the plasma of apolipoprotein E knockout mice was measured by enzyme-linked immunosorbent assay. Our results showed that inflammatory stress increased cholesterol accumulation in hepatic cells and in the livers of apolipoprotein E knockout mice. Further analysis showed that inflammatory stress increased the expression of low-density lipoprotein (LDL) receptor (LDLr), sterol regulatory element-binding protein (SREBP) cleavage activating protein (SCAP), and SREBP-2. Confocal microscopy showed that IL-1beta increased the translocation of SCAP/SREBP-2 complex from endoplasmic reticulum (ER) to Golgi in HepG2 cells, thereby activating LDLr gene transcription. IL-1beta, TNF-alpha, and systemic inflammation induced by casein injection also inhibited expression of adenosine triphosphate-binding cassette transporter A1 (ABCA1), peroxisome proliferator-activated receptor-alpha (PPAR-alpha), and liver X receptor-alpha (LXRalpha). This inhibitory effect may cause cholesterol efflux reduction.

Conclusion: Inflammatory stress up-regulates LDLr-mediated cholesterol influx and down-regulates ABCA1-mediated cholesterol efflux in vivo and in vitro. This may exacerbate the progression of NAFLD by disrupting cholesterol trafficking control, especially during the second hit phase of liver damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Apolipoproteins E / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cholesterol / metabolism*
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Fatty Liver / metabolism*
  • Fatty Liver / pathology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Hepatocytes / pathology
  • Humans
  • Inflammation / chemically induced
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Interleukin-1beta / adverse effects
  • Lipid Metabolism / drug effects
  • Lipid Metabolism / physiology*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Liver X Receptors
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Orphan Nuclear Receptors
  • PPAR alpha / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, LDL / metabolism
  • Tumor Necrosis Factor-alpha / adverse effects


  • ABCA1 protein, human
  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters
  • Apolipoproteins E
  • DNA-Binding Proteins
  • Interleukin-1beta
  • Liver X Receptors
  • NR1H3 protein, human
  • Nr1h3 protein, mouse
  • Orphan Nuclear Receptors
  • PPAR alpha
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, LDL
  • Tumor Necrosis Factor-alpha
  • Cholesterol