Increased Lipopolysaccharide Sensitivity in Alcoholic Fatty Livers Is Independent of Leptin Deficiency and Toll-Like Receptor 4 (TLR4) or TLR2 mRNA Expression

Authors

  • Laszlo Romics Jr,

    1. Liver Center, Department of Medicine (LR, PM, KK, AV, YD, AD, GS), University of Massachusetts Medical School, Worcester, Massachusetts.
    Search for more papers by this author
  • Pranoti Mandrekar,

    1. Liver Center, Department of Medicine (LR, PM, KK, AV, YD, AD, GS), University of Massachusetts Medical School, Worcester, Massachusetts.
    Search for more papers by this author
  • Karen Kodys,

    1. Liver Center, Department of Medicine (LR, PM, KK, AV, YD, AD, GS), University of Massachusetts Medical School, Worcester, Massachusetts.
    Search for more papers by this author
  • Arumugam Velayudham,

    1. Liver Center, Department of Medicine (LR, PM, KK, AV, YD, AD, GS), University of Massachusetts Medical School, Worcester, Massachusetts.
    Search for more papers by this author
  • Yvonne Drechsler,

    1. Liver Center, Department of Medicine (LR, PM, KK, AV, YD, AD, GS), University of Massachusetts Medical School, Worcester, Massachusetts.
    Search for more papers by this author
  • Angela Dolganiuc,

    1. Liver Center, Department of Medicine (LR, PM, KK, AV, YD, AD, GS), University of Massachusetts Medical School, Worcester, Massachusetts.
    Search for more papers by this author
  • Gyongyi Szabo

    Corresponding author
    1. Liver Center, Department of Medicine (LR, PM, KK, AV, YD, AD, GS), University of Massachusetts Medical School, Worcester, Massachusetts.
    Search for more papers by this author

Reprint requests: Gyongyi Szabo, MD, PhD, Professor of Medicine, Department of Medicine, University of Massachusetts Medical School, LRB 215, 364 Plantation St., Worcester, MA 01605-2324; Fax: (508) 856-4770; E-mail: gyongyi.szabo@umassmed.edu.

Abstract

Background:

Both alcoholic (AFL) and nonalcoholic (NAFL) fatty livers show increased sensitivity to endotoxin-induced injury. Lipopolysaccharide (LPS) is recognized by toll-like receptor 4 (TLR4), whereas lipopeptide triggers TLR2 to induce common downstream activation of nuclear factor (NF)-κB and pro-inflammatory pathways that are activated in AFL and NAFL.

Methods:

Serum alanine aminotransferase (ALT), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 levels; hepatic NF-κB activity; and expression of TLR2, TLR4, inducible nitric oxide synthase (iNOS), and heme oxygenase (HO)-1 mRNAs were investigated in lean and leptin-deficient ob/ob mice after LPS challenge in combination with acute or chronic alcohol feeding.

Results:

Increased LPS sensitivity in AFL and NAFL was characterized by elevated serum TNF-α and IL-6 induction. However, there was no difference in TLR2 and TLR4 mRNA levels between lean and ob/ob livers at baseline and after acute or chronic alcohol treatment. LPS increased TLR2, but not TLR4, mRNA levels in all groups. Chronic alcohol feeding and LPS increased serum ALT and TNF-α levels in lean but not in ob/ob mice compared with pair-fed controls. Hepatic NF-κB activation was increased in both ob/ob and lean mice after chronic alcohol feeding compared with pair-fed controls. Expression of iNOS, an inducer of oxidative stress, and HO-1, a cytoprotective protein, were higher in ob/ob compared with lean mice after chronic alcohol feeding. However, LPS-induced HO-1, but not iNOS, expression was attenuated in ob/ob compared with lean mice.

Conclusion:

These results imply that the increased sensitivity of AFL to LPS occurs without up-regulation of TLR2 or TLR4 genes and may be related to an imbalance of pro-inflammatory/oxidative and cytoprotective mechanisms.

Ancillary