To investigate whether hepatic lipid homeostasis would require STAT5-GR synergism or whether the two transcription factors would affect lipid metabolism independently, we conditionally deleted the GR (GRKO), STAT5 (S5KO), or STAT5 and the GR (double knockout [DKO]) in hepatocytes. Efficient deletion was confirmed by western blotting analyses (Supporting ). Macroscopic hepatomegaly and steatosis were first evident in 2-month-old S5KO and DKO mutants, as compared to GRKO and control mice. Although hepatomegaly in S5KO mutants remained stable, DKO mice displayed progressive fatty liver disease, with a 4-fold increase in liver mass by 12 months of age () and an 8-fold rise in hepatic triglyceride (TG) content as early as 2 months of age (). Strikingly, a dramatic depletion of white adipose tissue (WAT) was observed exclusively in DKO mice (−58%; ). Histological examination revealed a significantly increased mean score of steatosis in young (83% versus 49%), but not in aged, DKO mice, compared to age-matched S5KO mutants (77% versus 53%; Supporting ). Micro- and macrovesicular steatosis in S5KO () and DKO mice () was associated with elevated serum levels of alanine aminotransferase (ALT) and alkaline phosphatase (ALP) as indicators of liver injury (). In contrast, histological analysis revealed a normal liver architecture in control () and GRKO animals () at all time points analyzed. A summary of the histological analysis is given in Supporting Table 1. Taken together, the STAT5-dependent fatty degeneration of hepatocytes is severely aggravated upon additional GR deletion in the liver.
Growth hormone (GH)-activated signal transducer and activator of transcription 5 (STAT5) and the glucocorticoid (GC)-responsive glucocorticoid receptor (GR) are important signal integrators in the liver during metabolic and physiologic stress. Their deregulation has been implicated in the development of metabolic liver diseases, such as steatosis and progression to fibrosis. Using liver-specific STAT5 and GR knockout mice, we addressed their role in metabolism and liver cancer onset. STAT5 single and STAT5/GR double mutants developed steatosis, but only double-mutant mice progressed to liver cancer. Mechanistically, STAT5 deficiency led to the up-regulation of prolipogenic sterol regulatory element binding protein 1 (SREBP-1) and peroxisome proliferator activated receptor gamma (PPAR-γ) signaling. Combined loss of STAT5/GR resulted in GH resistance and hypercortisolism. The combination of both induced expression of adipose tissue lipases, adipose tissue lipid mobilization, and lipid flux to the liver, thereby aggravating STAT5-dependent steatosis. The metabolic dysfunctions in STAT5/GR compound knockout animals led to the development of hepatic dysplasia at 9 months of age. At 12 months, 35% of STAT5/GR-deficient livers harbored dysplastic nodules and ~60% hepatocellular carcinomas (HCCs). HCC development was associated with GH and insulin resistance, enhanced tumor necrosis factor alpha (TNF-α) expression, high reactive oxygen species levels, and augmented liver and DNA damage parameters. Moreover, activation of the c-Jun N-terminal kinase 1 (JNK1) and STAT3 was prominent.
Impairment of Hepatic Growth Hormone and …
Hepatic STAT5/GR signaling is crucial for the maintenance of systemic lipid homeostasis. Impairment of both signaling cascades causes severe metabolic liver disease and promotes spontaneous hepatic tumorigenesis. ( 2011;54:1398–1409)