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.

Activation of innate immune systems including Toll-like receptor (TLR) signaling is a key in chronic liver disease. Recent studies suggest that gut microflora-derived bacterial products (i.e. LPS, bacterial DNA) and endogenous substances (i.e. HMGB1, free fatty acids) released from damaged cells activate hepatic TLRs that contribute to the development of alcoholic (ASH) and non-alcoholic steatohepatitis (NASH) and liver fibrosis. The crucial role of TLR4, a receptor for LPS, has been implicated in the development of ASH, NASH, liver fibrosis and hepatocellular carcinoma. However, the role of other TLRs, such as TLR2 and TLR9 in chronic liver disease remains less clear. In this review, we will discuss the role of TLR2, 4 and 9 in Kupffer cells and hepatic stellate cells in the development of ASH, NASH and hepatocarcinogenesis.

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Hyaluronan (HA), a major extracellular matrix glycosaminoglycan, is a biomarker for cirrhosis. However, little is known about the regulatory and downstream mechanisms of HA overproduction in liver fibrosis. Hepatic HA and HA synthase 2 (HAS2) expression was elevated in both human and murine liver fibrosis. HA production and liver fibrosis were reduced in mice lacking HAS2 in hepatic stellate cells (HSCs), whereas mice overexpressing HAS2 had exacerbated liver fibrosis. HAS2 was transcriptionally up-regulated by transforming growth factor–β through Wilms tumor 1 to promote fibrogenic, proliferative, and invasive properties of HSCs via CD44, Toll-like receptor 4 (TLR4), and newly identified downstream effector Notch1. Inhibition of HA synthesis by 4-methylumbelliferone reduced HSC activation and liver fibrosis in mice. Our study provides evidence that HAS2 actively synthesizes HA in HSCs and that it promotes HSC activation and liver fibrosis through Notch1. Targeted HA inhibition may have potential to be an effective therapy for liver fibrosis.