bims-liverm 2023-01-22 papers

Issue of 2023–01–22
three papers selected by

Am J Physiol Gastrointest Liver Physiol. 2023 Jan 17.

Fibroblast Growth Factor 19 Secretion and Function in Perinatal Development.

Caitlin Vonderohe, Gregory Guthrie, Douglas G Burrin.

Limited work has focused on Fibroblast Growth Factor-19 (FGF19) secretion and function in the perinatal period. FGF19 is a potent growth factor that coordinates development of the brain, eye, inner ear and skeletal system in the embryo, but after birth, FGF19 transitions to be an endocrine regulator of the classic pathway of hepatic bile acid synthesis. FGF19 has emerged as a mediator of metabolism and bile acid synthesis in aged animals and adults in the context of liver disease and metabolic dysfunction. FGF19 has also been shown to have systemic insulin-sensitizing and skeletal muscle hypertrophic effects when induced or supplemented at supraphysiologic levels in adult rodent models. These effects could be beneficial to improve growth and nutritional outcomes in preterm infants, which are metabolically resistant to the anabolic effects of enteral nutrition. Existing clinical data on FGF19 secretion and function in the perinatal period in term and preterm infants has been equivocal. Studies in pigs show that FGF19 expression and secretion is upregulated with gestational age and points to molecular and endocrine factors that may be involved. Work focused on FGF19 in pediatric diseases suggests that augmentation of FGF19 secretion by activation of gut FXR signaling is associated with benefits in diseases such as short bowel syndrome, parenteral nutrition-associated liver disease, and biliary atresia. Future work should focus on characterization of FGF19 secretion and the mechanism underpinning the transition of FGF19 function as an embryologic growth factor to metabolic and bile acid regulator.

Keywords: Bile Acid; Development; FGF19; Perinatal

DOI: https://doi.org/10.1152/ajpgi.00208.2022

Acta Biochim Biophys Sin (Shanghai). 2023 Jan 04.

Lithocholic acid promotes skeletal muscle regeneration through the TGR5 receptor.

Lijuan Sun, Fan Li, Weihao Tan, Weijie Zhao, Yongxiang Li, Xiaotong Zhu, Ping Gao, Gang Shu, Songbo Wang, Qingyan Jiang, Lina Wang.

<p indent="0mm">Lithocholic acid (LCA) is a classical secondary bile acid formed by the metabolism of gut microbiota. The TGR5 receptor (also known as G protein-coupled receptor 1, GPBAR1) is an important bile acid membrane receptor that mediates a variety of metabolic processes <italic>in vivo</italic>. In recent years, most studies have focused on the role of bile acid receptors in the intestine and liver. However, there are few reports on its effect on skeletal muscle regeneration, and the specific mechanism remains unclear. Therefore, it is necessary to investigate the mechanism of the TGR5 receptor in the regulation of skeletal muscle regeneration. The results demonstrate that muscle injection with LCA significantly reduces the necrosis rate of injured muscle and improves muscle injury. Moreover, treatment of C2C12 cells with LCA significantly increases AKT/mTOR/FoxO3 phosphorylation through the TGR5 receptor, enhances MyoG transcription and reduces FBXO32 transcription. These findings indicate that LCA can activate the TGR5/AKT signaling pathway, inhibit protein degradation and promote protein synthesis to enhance the myogenic process and promote skeletal muscle regeneration. </p>.

Keywords: TGR5 receptor; differentiation; lithocholic acid; muscle injury; proliferation

DOI: https://doi.org/10.3724/abbs.2022201

Hepatology. 2023 Jan 03.

Liangjun Zhang, Qiong Pan, Lu Zhang, Haihan Xia, Junwei Liao, Xiaoxun Zhang, Nan Zhao, Qiaoling Xie, Min Liao, Ya Tan, Qiao Li, Jinfei Zhu, Ling Li, Shijun Fan, Jianwei Li, Chengcheng Zhang, Shi-Ying Cai, James L Boyer, Jin Chai.

BACKGROUND AND AIMS: Bile acids trigger a hepatic inflammatory response, causing cholestatic liver injury. Runt-related transcription factor-1 (RUNX1), primarily known as a master modulator in hematopoiesis, plays a pivotal role in mediating inflammatory responses. However, RUNX1 in hepatocytes is poorly characterized, and its role in cholestasis is unclear. Herein, we aimed to investigate the role of hepatic RUNX1 and its underlying mechanisms in cholestasis.
APPROACH AND RESULTS: Hepatic expression of RUNX1 was examined in cholestatic patients and mouse models. Mice with liver-specific ablation of Runx1 were generated. Bile duct ligation and 1% cholic acid diet were used to induce cholestasis in mice. Primary mouse hepatocytes and the human hepatoma PLC/RPF/5-ASBT cell line were used for mechanistic studies. Hepatic RUNX1 mRNA and protein levels were markedly increased in cholestatic patients and mice. Liver-specific deletion of Runx1 aggravated inflammation and liver injury in cholestatic mice induced by bile duct ligation or 1% cholic acid feeding. Mechanistic studies indicated that elevated bile acids stimulated RUNX1 expression by activating the RUNX1-P2 promoter through JAK/STAT3 signaling. Increased RUNX1 is directly bound to the promotor region of inflammatory chemokines, including CCL2 and CXCL2, and transcriptionally repressed their expression in hepatocytes, leading to attenuation of liver inflammatory response. Blocking the JAK signaling or STAT3 phosphorylation completely abolished RUNX1 repression of bile acid-induced CCL2 and CXCL2 in hepatocytes.
CONCLUSIONS: This study has gained initial evidence establishing the functional role of hepatocyte RUNX1 in alleviating liver inflammation during cholestasis through JAK/STAT3 signaling. Modulating hepatic RUNX1 activity could be a new therapeutic target for cholestasis.

DOI: https://doi.org/10.1097/HEP.0000000000000041