Transforming growth factor beta signaling in hepatocytes participates in steatohepatitis through regulation of cell death and lipid metabolism in mice

Abstract

Transforming growth factor (TGF)-β signaling activates Smad-dependent and TAK1-dependent signaling to regulate cell survival, proliferation, fibrosis, and tumorigenesis. The effects of TGF-β signaling on metabolic syndrome including non-alcoholic fatty liver disease remain elusive. Wild-type (WT) and hepatocyte specific TGF-β receptor type II-deficient (Tgfbr2ΔHEP) mice were fed a choline-deficient amino acid defined (CDAA) diet for 22 weeks to induce NASH. WT mice fed a CDAA diet displayed increased activation of Smad2/3 and had marked lipid accumulation, inflammatory cell infiltration, hepatocyte death, and fibrosis; in comparison, Tgfbr2ΔHEP mice fed a CDAA diet had suppressed liver steatosis, inflammation, and fibrosis. Both palmitate-induced steatotic hepatocytes and hepatocytes isolated from WT mice fed a CDAA diet had increased susceptibility to TGF-β-mediated death. TGF-β-mediated death in steatotic hepatocytes was inhibited by silencing Smad2 or blocking ROS production, and was enhanced by inhibiting TAK1 or NF-κB. Increased hepatic steatosis in WT mice fed a CDAA diet was associated with the increased expression of lipogenesis genes (Dgat1, Srebp1c), whereas the decreased steatosis in Tgfbr2ΔHEP mice was accompanied by the increased expression of genes involved in β-oxidation (Cpt1, Acox1). In combination with palmitate treatment, TGF-β signaling promoted lipid accumulation with induction of lipogenesis-related genes and suppression of β-oxidation-related genes in hepatocytes. Silencing Smad2 decreased TGF-β-mediated lipid accumulation and corrected altered gene expression related to lipid metabolism in hepatocytes. Finally, we confirmed that the livers from patients with non-alcoholic steatohepatitis displayed phosphorylation and nuclear-translocation of Smad2/3. Conclusions TGF-β signaling in hepatocytes contributes to hepatocyte death and lipid accumulation through Smad signaling and ROS production that promote the development of NASH.

Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression

“…Nrg4 treatment strongly attenuated cell death markers in primary hepatocytes expressing ErbB4. We measured the release of lactate dehydrogenase (LDH) into culture media as an indicator of hepatocyte death (38). LDH release by primary hepatocytes was markedly increased in response to PA/TNF-α treatment ( Figure 4C).…”

An insight into the key genes and biological functions associated with insulin resistance in adipose tissue with microarray technology

“…It has been proposed that upregulation of TGFBR2 induced by high extracellular glucose, may contribute to distal tubular hypertrophy in diabetic nephropathy (24). A study by Yang et al (25) demonstrated that TGF-β signaling in hepatocytes participates in steatohepatitis through the regulation of cell death and lipid metabolism. PTEN is a key negative regulator of insulin-stimulated glucose uptake in vitro and in vivo (26).…”

Liver and systemic insulin resistance

“…In fact, disruption of insulin receptor or Janus kinase 2 in hepatocytes results in hepatic steatosis and systemic IR, compared to WT mice. 2,3 In contrast, mice with liver-specific inactivation of p70S6K or protein tyrosine phosphatase 1B exhibited suppressed hepatic steatosis and IR. 4,5 These observations clearly indicate that the alteration of hepatic glucose and/or lipid metabolism affect systemic insulin sensitivity.…”

“…This pleiotropic cytokine, besides its known role in fibrogenesis, also directly acts on hepatocytes to induce steatosis, cell damage, and inflammation, the indispensable features of NASH. 2 Interestingly, they observed that alteration of hepatocyte TGFbR2-mediated signaling had peripheral effects outside the liver. CDAA-hepatocyte TGFbR2 2/2 mice presented a lower body weight, a better glucose tolerance, and a higher insulin sensitivity, compared to CDAA-fed wild-type mice, suggesting that hepatocyte TGF-b signaling and/or ensuing hepatocyte injury and liver inflammation affect whole-body insulin sensitivity.…”

“…Feeding mice a CDAA diet causes hepatic injury and perturbation in lipid metabolism with increased liver triglyceride storage and circulating free fatty acids. 2 However, it is not known to alter glucose homeostasis. As reported by the same group elsewhere, the homeostasis model assessment of IR index was similar in CDAA and control CSAA-fed animals, 3 questioning IR in the model and the physiological consequence of modification of insulin sensitivity and glucose tolerance observed upon hepatocyte-specific deletion TGFbR2.…”