Adiponectin deficiency impairs liver regeneration through attenuating STAT3 phosphorylation in mice

Abstract

Liver regeneration is a very complex and well-orchestrated process associated with signaling cascades involving cytokines, growth factors, and metabolic pathways. Adiponectin is an adipocytokine secreted by mature adipocytes, and its receptors are widely distributed in many tissues, including the liver. Adiponectin has direct actions in the liver with prominent roles to improve hepatic insulin sensitivity, increase fatty acid oxidation, and decrease inflammation. To test the hypothesis that adiponectin is required for normal progress of liver regeneration, 2/3 partial hepatectomy (PH) was performed on wild-type and adiponectin-null mice. Compared to wild-type mice, adiponectin-null mice displayed decreased liver mass regrowth, impeded hepatocyte proliferation, and increased hepatic lipid accumulation. Gene expression analysis revealed that adiponectin regulated the gene transcription related to lipid metabolism. Furthermore, the suppressed hepatocyte proliferation was accompanied with reduced signal transducer and activator of transcription protein 3 (STAT3) activity and enhanced suppressor of cytokine signaling 3 (Socs3) transcription. In conclusion, adiponectin-null mice exhibit impaired liver regeneration and increased hepatic steatosis. Increased expression of Socs3 and subsequently reduced activation of STAT3 in adiponectin-null mice may contribute to the alteration of the liver regeneration capability and hepatic lipid metabolism after PH. The liver has a central role in metabolic homeostasis, as it is responsible for the metabolism, synthesis, storage, and redistribution of nutrients, carbohydrates, fats, and vitamins. Paradoxically, it is also the main detoxifying organ of the body, which is frequently challenged by chemical, traumatic, or infectious injuries. Consequently, the liver has evolved a unique ability to regenerate in respond to liver mass loss because of injuries. 1,2 Liver regeneration, which is driven by the replication of existing hepatocytes, is a process of compensatory hyperplasia rather than a differentiation process of stem cells. 3 One of the most effective models for studying liver regeneration after hepatocellular loss is partial hepatectomy (PH) in rodents. This technique, which was first described by Higgins and Anderson and performed in rats, 4 can be modified to be safely and reproducibly performed in mice. 5 After PH, resection of about 2/3 of liver mass results in quiescent hepatocytes rapidly re-entering the cell cycle. This highly regulated process is primed by different cytokines and growth factors that activate the downstream kinases and transcription factors. As a result, the hepatocytes initiate the transcription of more than 100 early genes, accumulate triglyceride and cholesterol to supply the energy and materials required for restore the liver mass. After one or two rounds of replication of hepatocytes, the original liver mass is restored within 5-7 days. Thus, liver regeneration constitutes a unique model to study signal transduction, lipid metabolism, and cell cycl...

Adiponectin as a tissue regenerating hormone: more than a metabolic function

“…During liver regeneration in adiponectin KO mice, hepatic cells exhibit delayed DNA replication and increased lipid accumulation, suggesting a possible involvement of altered fat metabolism during liver regeneration [77]. In agreement, Shu et al [78] show that adiponectin KO mice display decreased liver mass growth, hindered hepatocyte proliferation, and increased hepatic lipid accumulation. The deletion or the overexpression of fAd in mouse model reveals a specific role of adiponectin in promoting functional renal recovery after podocyte ablation [79].…”

“…In the bone, fAd promotes the differentiation of mesenchymal progenitors into osteoblasts [77]. In the endothelium, fAd promotes the enhancement of proliferation and the migration of keratinocytes [88], ameliorates wound repair in adiponectin-deficient and diabetic db/db mice [88] and increases the recruitment of endothelial cell precursors [78] differentiation towards a mature endothelium, adhesive properties [86], proliferative rate [87,88], and capacity to be incorporated into vascular structures [89]. Recent findings suggest that T2 DM and subsequent oxidative damage impede the interaction between the vascular wall and normal ePC through a mechanism that could be reversed by heme-oxygenase-1, fAd, and phospho-AMPK [82].…”

The interaction of hepatic lipid and glucose metabolism in liver diseases

“…However, hyperactivation of autophagy induces cell death, and the necrosis rate is actually a predictor of liver failure [9,112]. Furthermore, as we previously elucidated key processes in the interplay between adipose tissue and the liver, adiponectin was identified as an important mediator of STAT3 signaling in the regenerating liver [113,114].…”

Adiponectin suppresses endoplasmic reticulum stress in nonalcoholic steatohepatitis

“…Adiponectin has direct actions in the liver with prominent roles in improving hepatic insulin sensitivity, increasing fatty acid oxidation and decreasing inflammation. Adiponectin-null mice exhibit impaired liver regeneration and increased hepatic steatosis (24). Yoshiuchi et al directly evaluated the effects of the diabetic agent pioglitazone on in vivo ER stress under diabetic conditions.…”