title: Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2.
abstract: 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.
authors.affiliation: Cardiovascular Research Institute, UCSF, San Francisco, California 94158-9001, USA.
authors.forename: Brandon C
authors.initials: BC
authors.lastname: Sos
authors.forename: Charles
authors.initials: C
authors.lastname: Harris
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Nordstrom
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Tran
authors.forename: Mercedesz
authors.initials: M
authors.lastname: Balázs
authors.forename: Patrick
authors.initials: P
authors.lastname: Caplazi
authors.forename: Maria
authors.initials: M
authors.lastname: Febbraio
authors.forename: Milana A B
authors.initials: MA
authors.lastname: Applegate
authors.forename: Kay-Uwe
authors.initials: KU
authors.lastname: Wagner
authors.forename: Ethan J
authors.initials: EJ
authors.lastname: Weiss
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D017353:Gene Deletion; D013006:Growth Hormone / Q000378:metabolism*; D022781:Hepatocytes / Q000502:physiology; D053614:Janus Kinase 2 / Q000172:deficiency* / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009928:Organ Specificity; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D014280:Triglycerides / Q000378:metabolism
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D018955:CD36 Antigens; D005230:Fatty Acids, Nonesterified; D047495:PPAR gamma; D014280:Triglycerides; D013006:Growth Hormone; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2