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Bacterial lipopolysaccharide induces uncoupling protein-2 expression in hepatocytes by a tumor necrosis
H Cortez-Pinto1, S Q Yang, H Z Lin
1Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Abstract:
The liver is a target for bacterial lipopolysaccharide (LPS) and participates in the metabolic response to endotoxemia. Recently published evidence indicates that LPS increases the expression of mitochondrial uncoupling protein-2 (UCP-2) mRNAs in several tissues, including the liver. Because hepatocytes in the healthy liver do not express UCP-2, LPS was thought to induce UCP-2 in liver macrophages, which express UCP-2 constitutively. However, the present studies of cultured peritoneal macrophages indicate that LPS reduces steady state levels of UCP-2 mRNAs in these cells. In contrast, UCP-2 mRNAs are induced in hepatocytes isolated from LPS treated rats and transfection of these hepatocytes with UCP-2 promoter-reporter constructs demonstrates substantial increases in UCP-2 promoter activity. LPS induction of hepatocyte UCP-2 expression is virtually abolished by prior treatment of rats with neutralizing antibodies to tumor necrosis factor alpha (TNF). Futhermore, TNFalpha treatment induces UCP-2 mRNA accumulation in primary cultures of hepatocytes from healthy rats. Thus, hepatocytes are likely to be important contributors to endotoxin-related increases in liver UCP-2 via a mechanism that involves the LPS-inducible cytokine, TNFalpha.
Insights
Bacterial lipopolysaccharide (LPS) induces mitochondrial uncoupling protein-2 (UCP-2) in liver cells, not macrophages. Tumor necrosis factor alpha (TNF) mediates this LPS effect in hepatocytes, impacting endotoxemia response.
Area of Science:
- Hepatology
- Immunology
- Molecular Biology
Background:
- The liver responds metabolically to bacterial lipopolysaccharide (LPS) during endotoxemia.
- LPS is known to increase mitochondrial uncoupling protein-2 (UCP-2) mRNA expression in various tissues.
- Previously, it was assumed LPS-induced UCP-2 in the liver primarily involved macrophages.
Purpose of the Study:
- To investigate the specific cell types in the liver responsible for increased UCP-2 expression following LPS exposure.
- To elucidate the role of tumor necrosis factor alpha (TNF) in LPS-mediated UCP-2 induction in hepatocytes.
Main Methods:
- Primary hepatocyte and peritoneal macrophage cultures were used.
- Quantitative analysis of UCP-2 mRNA levels after LPS treatment.
- UCP-2 promoter-reporter assays in transfected hepatocytes.
- In vivo studies using neutralizing antibodies to TNFalpha and in vitro TNFalpha treatment.
Main Results:
- LPS treatment decreased UCP-2 mRNA levels in cultured macrophages.
- LPS induced UCP-2 mRNA and promoter activity in isolated hepatocytes.
- Antibodies neutralizing TNFalpha abolished LPS-induced UCP-2 expression in vivo.
- TNFalpha treatment alone increased UCP-2 mRNA in hepatocytes.
Conclusions:
- Hepatocytes, not macrophages, are the primary source of increased liver UCP-2 in response to LPS.
- The induction of hepatocyte UCP-2 by LPS is mediated by the cytokine TNFalpha.
- This pathway highlights a significant cellular mechanism in the liver's metabolic response to endotoxemia.