Liver-specific Deletion of the Growth Hormone Receptor Reveals Essential Role of Growth Hormone Signaling in Hepatic Lipid Metabolism

Fan, Yong; Menon, Ram K.; Cohen, Pinchas; Hwang, David; Clemens, Thomas L.; DiGirolamo, Douglas J.; Kopchick, John J.; Roith, Derek Le; Trucco, Massimo; Sperling, Mark A.

doi:10.1074/jbc.m109.014308

Cited by 240 publications

(227 citation statements)

References 30 publications

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“…95) between the two measurements in the combined data are consistent with the above observations. Just as circulating (liver-derived) IGF1 is extracted by the kidney (D'Ercole et al 1984, Kimura et al 1994) and appears to induce gene expression of renal growth factors (Fan et al 2009), it is possible that CNP plays a similar role in the immature kidney. While contributions of CNPs from the kidney and other non-skeletal tissues to circulating levels are likely, our current observations support previous findings of a positive venoarterial CNP gradient across bone dense tissues ) and the correlation of NTproCNP with linear growth velocity in a wide variety of clinical settings.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamic responses of plasma and tissue C-type natriuretic peptide to GH: correlation with linear growth in GH-deficient rats

Prickett

Bothwell²,

Yandle³

et al. 2011

Journal of Endocrinology

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Studies from genetic modification and spontaneous mutations show that C-type natriuretic peptide (CNP) signalling plays an essential part in postnatal endochondral growth, but measurement of CNP proteins and changes in their abundance in tissues and plasma during normal growth has not been reported. Using rodent pups with GH deficiency, we now describe the pharmacodynamic response of CNP and rat amino-terminal proCNP (NTproCNP) in plasma and tissues, and relate these to changes in linear growth (nose-tail length, tibial length and tibial growth plate width) during the course of 1 week of GH or saline (control) administration. Compared with saline, significant increases in plasma and tissue CNP forms were observed after 24 h in GH-treated pups and before any detectable change in linear growth. Whereas CNP abundance was increased in most tissues (muscle, heart and liver) by GH, enrichment was the greatest in extracts from growth plates and kidney. Plasma and tissue concentrations in GH-treated pups were sustained or further increased at 1 week when strong positive associations were found between plasma NTproCNP and linear growth or tissue concentrations. High content of NTproCNP in kidney tissue strongly correlated with plasma concentrations, which is consistent with previous data showing renal extraction of the peptide. In showing a prompt and significant increase in CNP in tissues driving normal endochondral growth, these findings provide further rationale for CNP agonists in the treatment of growth disorders resistant to current therapies and support the use of CNP concentrations as biomarkers of linear growth.

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Section: Discussionmentioning

confidence: 99%

Pharmacodynamic responses of plasma and tissue C-type natriuretic peptide to GH: correlation with linear growth in GH-deficient rats

Prickett

Bothwell²,

Yandle³

et al. 2011

Journal of Endocrinology

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“…Moreover, we found that DLK1-overexpressing mice had elevated production of pituitary growth hormone due to a local defect in IGF1 feedback. Because impaired GH signaling is known to cause steatosis by affecting pathways of hepatic lipid import and synthesis (3)(4)(5), as well affecting peripheral FA oxidation (22), we propose that increased dosage of DLK1 acts primarily on the GH axis to shift the metabolic mode toward FA oxidation, with overall beneficial effects on hepatic lipid deposition.…”

Section: Significancementioning

confidence: 99%

“…Depletion of hepatic GH signaling is thought to cause accumulation of triglycerides in the liver in two ways. Firstly, ablation of GH signaling in the liver itself prevents suppression of the fatty acid translocase Cd36, and Pparγ, resulting in increased FA import and biosynthesis (3)(4)(5). Secondly, ablation of GHstimulated hepatic IGF1 release causes elevated circulating GH that induces expression of adipose tissue lipases, adipose tissue lipid mobilization, and lipid flux to the liver (5).…”

Section: Elevated Dlk1 Protects Against High Fat Diet-induced Steatosmentioning

confidence: 99%

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DLK1/PREF1 regulates nutrient metabolism and protects from steatosis

Charalambous

Rocha

Radford

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Hepatosteatosis or nonalcoholic fatty liver disease (NAFLD) is an important health problem affecting approximately 20% of the population of the United States and is associated with cardiovascular risk factors such as insulin resistance and obesity. Using a Delta-like homologue (Dlk1) [also known as preadipocyte factor 1 (Pref1)] transgenic model, we identified a new player in the growth hormone (GH) signaling pathway that, when overexpressed, is protective against obesity and hepatosteatosis. Because the dosage of circulating DLK1 is naturally elevated in early life and during pregnancy, we believe that our transgenic model mimics endogenous mechanisms of DLK1-mediated GH signaling modulation that are used during periods of metabolic stress to protect from steatosis and alter fuel utilization in the whole organism.

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“…1F). To determine the effect of APOC3 on hepatic VLDL-TG production, we determined hepatic VLDL-TG production in APOC3-tg versus WT mice, using tyloxapol to inhibit systemic TG clearance, as described (45,46). APOC3-tg mice had significantly higher plasma TG levels at all time points after tyloxapol administration (Fig.…”

Section: Effect Of Apoc3 On the Pathogenesis Of Nafld In Apoc3-tgmentioning

confidence: 99%

APOC3 Protein Is Not a Predisposing Factor for Fat-induced Nonalcoholic Fatty Liver Disease in Mice

Cheng

Yamauchi

Lee

et al. 2017

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinNonalcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation in liver, is prevalent in obesity. Genetic factors that link obesity to NAFLD remain obscure. Apolipoprotein C3 (APOC3) is a lipid-binding protein with a pivotal role in triglyceride metabolism. Humans with APOC3 gain-of-function mutations and mice with APOC3 overproduction are associated with hypertriglyceridemia. Nonetheless, it remains controversial whether APOC3 is culpable for diet-induced NAFLD. To address this fundamental issue, we fed APOC3-transgenic and wild-type littermates a high fructose diet or high fat diet, followed by determination of the effect of APOC3 on hepatic lipid metabolism and inflammation and the progression of NAFLD. To gain mechanistic insight into NAFLD, we determined the impact of APOC3 on hepatic triglyceride synthesis and secretion versus fatty acid oxidation. APOC3-transgenic mice were hypertriglyceridemic, culminating in marked elevation of triglycerides, cholesterols, and nonesterified fatty acids in plasma. Despite the prevailing hypertriglyceridemia, APOC3-transgenic mice, relative to wild-type littermates, had similar weight gain and hepatic lipid content without alterations in hepatic expression of key genes involved in triglyceride synthesis and secretion and fatty acid oxidation. APOC3-transgenic and wild-type mice had similar Kupffer cell content without alterations in hepatic expression of pro-and anti-inflammatory cytokines. APOC3 neither exacerbated dietinduced adiposity nor aggravated the degree of steatosis in high fructose or high fat-fed APOC3-transgenic mice. These effects ensued independently of weight gain even after 10-month high fat feeding. We concluded that APOC3, whose dysregulation is liable for hypertriglyceridemia, is not a predisposing factor for linking overnutrition to NAFLD in obesity. Nonalcoholic fatty liver disease (NAFLD)4 is characterized by excessive lipid deposition in the liver of subjects with little alcohol consumption. Patients with NAFLD are at heightened risk of developing steatohepatitis with potential complications of fibrosis and cirrhosis (1-4). Currently, NAFLD affects about 30% of the general population, and its prevalence is increasing along with the rising epidemic of obesity in both adults and children (1, 5-10). Although it is known that NAFLD results from increased lipogenesis and decreased fatty acid oxidation in the liver, accompanied often by hepatic overproduction of TG-rich very low density lipoprotein (VLDL-TG), genetic factors that tip the balance of these three intertwining pathways in hepatic lipid metabolism at the expense of NAFLD are incompletely characterized.Apolipoprotein C3 (APOC3) (79 amino acids in length) is one of the most abundant apolipoproteins in the blood, where it is present as an exchangeable moiety between high density lipoproteins (HDLs) and triglyceride (TG)-rich particles, such as VLDL and chylomicrons (11). Secreted mainly from the liver and to a lesser extent from the intestine, AP...

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Liver-specific Deletion of the Growth Hormone Receptor Reveals Essential Role of Growth Hormone Signaling in Hepatic Lipid Metabolism

Cited by 240 publications

References 30 publications

Pharmacodynamic responses of plasma and tissue C-type natriuretic peptide to GH: correlation with linear growth in GH-deficient rats

Pharmacodynamic responses of plasma and tissue C-type natriuretic peptide to GH: correlation with linear growth in GH-deficient rats

DLK1/PREF1 regulates nutrient metabolism and protects from steatosis

APOC3 Protein Is Not a Predisposing Factor for Fat-induced Nonalcoholic Fatty Liver Disease in Mice

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