Gastroenterology

Gastroenterology

Volume 116, Issue 5, May 1999, Pages 1184-1193
Gastroenterology

Liver, Pancreas, and Biliary Tract
Lipids up-regulate uncoupling protein 2 expression in rat hepatocytes,☆☆

https://doi.org/10.1016/S0016-5085(99)70022-3Get rights and content
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Abstract

Background & Aims: Hepatic steatosis reflects the accumulation of triglycerides and free fatty acids in hepatocytes. Although lipids and their metabolites are potentially hepatotoxic, the absence of overt injury in fatty livers suggests that adaptive responses to lipid accumulation occur. Fatty acids induce mitochondrial uncoupling proteins (UCP) 2 and 3 in muscle and fat, providing a mechanism to dispose of excessive fatty acids. Although hepatocytes do not normally express uncoupling proteins, UCP-2 is expressed in hepatocytes of genetically obese mice with fatty livers, suggesting that lipids also induce UCP-2 in hepatocytes. Methods: To test whether lipids up-regulate hepatocyte UCP-2, cultures of rat hepatocytes were treated with lipid emulsions, linoleic or oleic acid, and UCP-2 expression was evaluated by Northern blotting and immunocytochemistry. Because increased reactive oxygen species (ROS) production may contribute to lipid-related UCP-2 induction, the DNA-binding activity of the ROS-activated transcription factor, NF-κB, was measured, and the effects of tert-butyl hydroperoxide (TBHP) and glutathione (GSH) on UCP-2 induction were also assessed. Results: Lipid emulsions increased the DNA-binding activity of NF-κB and resulted in a dose- and time-dependent induction of UCP-2 transcripts in cultured hepatocytes; after 24 hours, UCP-2 messenger RNA levels were increased 4.5-fold, and increased UCP-2 protein was shown by immunocytochemistry. Consistent with the possibility that ROS generated intracellularly during lipid metabolism participates in UCP-2 induction, addition of the cell-impermeable antioxidant GSH did not alter lipid-related induction of UCP-2. Furthermore, TBHP, which is known to increase hepatocyte mitochondrial ROS production, also increased UCP-2 messenger RNA levels. Conclusions: Lipids increase ROS and induce UCP-2 in hepatocytes. Thus, the liver may adapt to an excessive supply of lipid substrates by inducing UCP-2 to facilitate substrate disposal while constraining ROS production.

GASTROENTEROLOGY 1999;116:1184-1193

Abbreviations

GSH
glutathione
LPS
lipopolysaccharide
PPAR
peroxisome proliferator–activating receptors
ROS
reactive oxygen species
TBPH
tert-butyl hydroperoxide
TNF
tumor necrosis factor
UCP
uncoupling protein

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Address requests for reprints to: Anna Mae Diehl, M.D., Johns Hopkins University, 912 Ross Building, 720 Rutland Street, Baltimore, Maryland 21205. e-mail: [email protected]; fax: (410) 955-9677.

☆☆

Supported in part by a grant from the “Fundacao Luso-Americana para o Desenvolvimento” (to H.C.P.) and by ROIDK53792 (to A.M.D.).