Growth Hormone Mediates Its Protective Effect in Hepatic Apoptosis through Hnf6

Abstract

Background and AimsGrowth hormone (GH) not only supports hepatic metabolism but also protects against hepatocyte cell death. Hnf6 (or Oc1) belonging to the Onecut family of hepatocyte transcription factors known to regulate differentiated hepatic function, is a GH-responsive gene. We evaluate if GH mediates Hnf6 activity to attenuate hepatic apoptotic injury.MethodsWe used an animal model of hepatic apoptosis by bile duct ligation (BDL) with Hnf6 -/- (KO) mice in which hepatic Hnf6 was conditionally inactivated. GH was administered to adult wild type WT and KO mice for the 7 days of BDL to enhance Hnf6 expression. In vitro, primary hepatocytes derived from KO and WT liver were treated with LPS and hepatocyte apoptosis was assessed with and without GH treatment.ResultsIn WT mice, GH treatment enhanced Hnf6 expression during BDL, inhibited Caspase -3, -8 and -9 responses and diminished hepatic apoptotic and fibrotic injury. GH-mediated upregulation of Hnf6 expression and parallel suppression of apoptosis and fibrosis in WT BDL liver were abrogated in KO mice. LPS activated apoptosis and suppressed Hnf6 expression in primary hepatocytes. GH/LPS co-treatment enhanced Hnf6 expression with corresponding attenuation of apoptosis in WT-derived hepatocytes, but not in KO hepatocytes. ChiP-on-ChiP and electromobility shift assays of KO and WT liver nuclear extracts identified Ciap1 (or Birc2) as an Hnf6-bound target gene. Ciap1 expression patterns closely follow Hnf6 expression in the liver and in hepatocytes.ConclusionGH broad protective actions on hepatocytes during liver injury are effected through Hnf6, with Hnf6 transcriptional activation of Ciap1 as an underlying molecular mediator.

Outcomes after multiple courses of granulocyte colony‐stimulating factor and growth hormone in decompensated cirrhosis: A randomized trial

“…(11,33) Recently, GH has shown to prevent liver injury by inhibiting apoptosis through the hnf6 pathway. (34) However, we did not find additional benefit of GH in the present study, which may be because of the low dose of GH and small numbers. Improvement in liver functions, including CTP, MELD, serum albumin, HE, and ascites control, in this study also reflects the outcomes of enhanced LR.…”

“…GH also contributes to LR through the Foxm1b pathway and increasing cyclin proteins: Cdc25A, Cdc25B, and cyclin B1 and reducing cyclin‐dependent kinase p27 by acting on its residual receptors on hepatocytes . Recently, GH has shown to prevent liver injury by inhibiting apoptosis through the hnf6 pathway . However, we did not find additional benefit of GH in the present study, which may be because of the low dose of GH and small numbers.…”

Host Transcription Factors in Hepatitis B Virus RNA Synthesis

“…Figure 3E represents a high-resolution structure of mouse HNF6 bound with transthyretin promoter [204]. It plays key roles in many critical cellular processes such as pancreas development, suppression of cancer cell growth, cell differentiation, morphogenesis, lipid metabolism, and growth hormone production [238][239][240][241][242].…”

Impact of the growth hormone and IGF-1 on graft function and immune response in pediatric liver recipients

“…Кроме того, гормон роста предотвращает развитие апоптоза лимфоцитов, увеличивая продукцию NO, снижая синтез каспаз, участвующих в процессе апоптоза, а также способствуя полимеризации тубулина, что стабилизирует сеть микротрубочек [36]. Результаты экспериментальных исследований показали, что гормон роста защищает иммунные клетки от иммунодепрессивного действия глюкокортикоидов.…”