First published August 1, 2011 - More info
Non-alcoholic fatty liver disease is associated with multiple comorbid conditions, including diabetes, obesity, infection, and malnutrition. Mice with hepatocyte-specific disruption of growth hormone (GH) signaling develop fatty liver (FL), although the precise mechanism underlying this finding remains unknown. Because GH signals through JAK2, we developed mice bearing hepatocyte-specific deletion of JAK2 (referred to herein as JAK2L mice). These mice were lean, but displayed markedly elevated levels of GH, liver triglycerides (TGs), and plasma FFAs. Because GH is known to promote lipolysis, we crossed GH-deficient little mice to JAK2L mice, and this rescued the FL phenotype. Expression of the fatty acid transporter CD36 was dramatically increased in livers of JAK2L mice, as was expression of Pparg. Since GH signaling represses PPARγ expression and Cd36 is a known transcriptional target of PPARγ, we treated JAK2L mice with the PPARγ-specific antagonist GW9662. This resulted in reduced expression of liver Cd36 and decreased liver TG content. These results provide a mechanism for the FL observed in mice with liver-specific disruption in GH signaling and suggest that the development of FL depends on both GH-dependent increases in plasma FFA and increased hepatic uptake of FFA, likely mediated by increased expression of CD36.
Brandon C. Sos, Charles Harris, Sarah M. Nordstrom, Jennifer L. Tran, Mercedesz Balázs, Patrick Caplazi, Maria Febbraio, Milana A.B. Applegate, Kay-Uwe Wagner, Ethan J. Weiss
Original citation: J. Clin. Invest. 2011;121(4):1412–1423. doi:10.1172/JCI42894.
Citation for this corrigendum: J. Clin. Invest. 2011;121(8):3360. doi:10.1172/JCI59854.
The dosage for GW9662 was incorrectly noted in Results, Methods, and the legend for Figure 6. The correct sentences appear below.
Results: We treated a cohort of younger animals for 2 weeks at a dose of 4 mg/kg body weight and found that there was a 31% reduction in the expression of Cd36 (Figure 6F) and a 48% reduction in liver TG content in JAK2L animals treated with GW9662 versus those treated with vehicle (Figure 6G).
Methods: Each day, an aliquot of stock drug was thawed and then resuspended in DMSO/saline at a final concentration of 4 mg/kg body weight in a final volume of 100 μl.
Figure 6 legend: (F) Normalized expression of Cd36 from livers of male control and JAK2L mice after a 2-week treatment with the PPARγ-specific antagonist GW9662 (G) (4 mg/kg) or vehicle (V) (n = 5 for each group).
The authors regret the error.