Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice

Abstract

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.ConclusionHepatic 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. (hepatology 2011;54:1398–1409)

Reply

“…Moreover, the presence of the Cre transgene in GR AlfpCre mice does not lead to hepatic steatosis and up-regulation of genes involved in hepatic lipid synthesis and uptake. 1 Second, our data resemble findings published by the Hennighausen laboratory, which report that Stat5 deletion causes hepatic steatosis and carcinoma formation using Alb-Cre mice. 2,3 Additionally, we examined body weights of 2-month-old Stat5 loxP/loxP ;GR loxP/loxP ;Tg:AlfpCre/0, Stat5 flox/1 ;GR loxP/1 , and Stat5 loxP/1 ;GR loxP/1 ; Tg:AlfpCre/0 male littermates.…”

Sexual dimorphism in cancer

“…GH in turn targets the liver in a sexspecific manner, which is particularly evident in rodents at puberty, but is also found in humans 90 . GH function is mediated by the transcriptional activator STAT5, which can protect hepatocytes from chronic injuries and malignant transformation 12 , providing another possible mechanism for sexual dimorphism in HCC development.…”

The glucocorticoid receptor: cause of or cure for obesity?

“…In both prior works, reduced hepatic GR activity also resulted in hypercortisolism due to compensation by the hypothalamic-pituitary-adrenal (HPA) axis in response to peripheral glucocorticoid insensitivity. Liver-specific GR-knockout mice also display increased corticosteroid-binding globulin, which keeps the circulating GCs in an inactive form, thereby further inducing compensatory activation of the HPA axis (46). In Cushing's disease, hypercortisolism commonly leads to hepatic steatosis (53).…”

“…These facts suggest that GC overstimulation may also contribute to steatosis. Indeed, Mueller et al (46) demonstrated that hypercortisolism due to GR deletion from hepatocytes caused increased GR activation in adipocytes, which consequently led to increased lipolysis via upregulation of ATGL and HSL and reduction of perilipins. This phenomenon ultimately results in the overall diminution of adipose storage and the subsequent elevation of circulating FFAs, which accumulate in the liver (46).…”