Obesity-related fatty liver is unchanged in mice deficient for mitochondrial uncoupling protein 2.
Nonalcoholic fatty liver disease (NAFLD), a prevalent condition associated with obesity, has the potential of evolving into end-stage liver disease. The biochemical mechanisms that define the progression of NAFLD are not well known, but reactive oxygen species (ROS) have been implicated in this process. Uncoupling protein (UCP) 2 is a mitochondrial inner-membrane protein that mediates proton leak, uncouples adenosine triphosphate (ATP) synthesis, and negatively regulates ROS production. UCP2 expression is increased in various animal models of NAFLD. Up-regulation of UCP2 may compromise cellular ATP levels and worsen liver damage, or it may be protective by ROS reduction in NAFLD. This study aimed to obtain a definitive answer as to whether increased UCP2 expression contributes to NAFLD. UCP2-/- mice were exposed to obesity by crossbreeding with ob/ob mice and by long-term high-fat feeding to study the effect of UCP2 deficiency on the outcome of NAFLD. Steatohepatitis score of crossbred mice (ob/ob/ko) was similar to that of ob/ob mice at 25 weeks. No compensatory increase was observed in the expression of UCP5 in ob/ob/ko livers. To unmask the effects of absent leptin and its potential proinflammatory actions, steatosis was also induced in UCP2-/- mice by a high-fat diet continued for 6 months. Serum alanine aminotransferase (ALT) levels remained normal, and the steatohepatitis score in UCP2-/- mice was the same as in wild-type controls. We conclude that increased expression of UCP2 in the livers of mice with genetically or diet-induced obesity exerts neither protective nor deleterious effects on the severity of fatty liver disease.
Baffy
György
G
Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. Gyorgy_Baffy@brown.edu
Zhang
Chen-Yu
CY
Glickman
Jonathan N
JN
Lowell
Bradford B
BB
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D005234:Fatty Liver / Q000209:etiology* / Q000473:pathology; D007473:Ion Channels; D008099:Liver / Q000502:physiology; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D024101:Mitochondrial Proteins; D000071245:Mitochondrial Uncoupling Proteins; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009765:Obesity / Q000150:complications* / Q000235:genetics; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D000071246:Uncoupling Protein 2; D015854:Up-Regulation
D002352:Carrier Proteins; D004041:Dietary Fats; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D000071245:Mitochondrial Uncoupling Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; C492124:Slc25a14 protein, mouse; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2