ARRB1 inhibits non-alcoholic steatohepatitis progression by promoting GDF15 maturation.

Non-alcoholic steatohepatitis (NASH) is associated with the dysregulation of lipid metabolism and hepatic inflammation. The causal mechanism underlying NASH is not fully elucidated. This study investigated the role of β-Arrestin1 (ARRB1) in the progression of NASH. Liver tissue from patients with NASH and controls were obtained to evaluate ARRB1 expression. NASH models were established in Arrb1-knockout and wild-type mice fed either a high-fat diet (HFD) for 26 weeks or a methionine/choline-deficient (MCD) diet for 6 weeks. ARRB1 expression was reduced in liver samples from patients with NASH. Reduced Arrb1 levels were also detected in murine NASH models. Arrb1 deficiency accelerated steatohepatitis development in HFD-/MCD-fed mice (accompanied by the upregulation of lipogenic genes and downregulation of β-oxidative genes). Intriguingly, ARRB1 was found to interact with growth differentiation factor 15 (GDF15) and facilitated the transportation of GDF15 precursor (pro-GDF15) to the Golgi apparatus for cleavage and maturation. Treatment with recombinant GDF15 ablated the lipid accumulation in the presence of Arrb1 deletion both in vitro and in vivo. Re-expression of Arrb1 in the NASH models ameliorated the liver disease, and this effect was greater in the presence of pro-GDF15 overexpression. By contrast, the effect of pro-GDF15 overexpression alone was impaired in Arrb1-deficient mice. In addition, the severity of liver disease in patients with NASH was negatively correlated with ARRB1 expression. ARRB1 acts as a vital regulator in the development of NASH by facilitating the translocation of GDF15 to the Golgi apparatus and its subsequent maturation. Thus, ARRB1 is a potential therapeutic target for the treatment of NASH. Non-alcoholic steatohepatitis (NASH) is associated with the progressive dysfunction of lipid metabolism and a consequent inflammatory response. Decreased ARRB1 is observed in patients with NASH and murine NASH models. Re-expression of Arrb1 in the murine NASH model ameliorated liver disease, an effect which was more pronounced in the presence of pro-GDF15 overexpression, highlighting a promising strategy for NASH therapy.

Zhang Z ，Xu X ，Tian W ，Jiang R ，Lu Y ，Sun Q ，Fu R ，He Q ，Wang J ，Liu Y ，Yu H ，Sun B ... -  《-》

Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice.

Kim KH ，Kim SH ，Han DH ，Jo YS ，Lee YH ，Lee MS ... -  《Scientific Reports》

β(7)-Integrin and MAdCAM-1 play opposing roles during the development of non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease in Western countries. It is unclear how infiltrating leukocytes affect NASH-development. Our study aims to investigate the role of the homing/receptor, pair mucosal addressin cell adhesion molecule-1 (MAdCAM-1)/β7-Integrin, on immune cell recruitment and disease progression in a steatohepatitis model. Constitutive β7-Integrin deficient (β7-/-) and MAdCAM-1 deficient (MAdCAM-1-/-) mice were fed a high fat diet (HFD) for 26weeks or methionine-choline-deficient-diet (MCD) for 4weeks. β7-/- mice displayed earlier and more progressive steatohepatitis during HFD- and MCD-treatment, while MAdCAM-1-/- mice showed less histomorphological changes. The anti-oxidative stress response was significantly weaker in β7-/- mice as reflected by a significant downregulation of the transcription factors nuclear-factor(erythroid-derived 2)-like 2 (Nrf2) and heme-oxigenase-1 (HO-1). Additionally, stronger dihydroethidium-staining revealed an increased oxidative stress response in β7-/- animals. In contrast, MAdCAM-1-/- mice showed an upregulation of the anti-oxidative stress response. β7-/- animals exhibited stronger hepatic infiltration of inflammatory cells, especially neutrophils, reflecting earlier steatohepatitis initiation. Expression of regulatory T cell (TReg) markers as well as numbers of anti-inflammatory macrophages was significantly enhanced in MAdCAM-1-/- mice. Those changes finally resulted in earlier and stronger collagen accumulation in β7-/- mice, whereas MAdCAM-1-/- mice were protected from fibrosis initiation. Adhesion molecule mediated effector cell migration contributes to the outcome of steatohepatitis in the HFD- and the MCD model. While MAdCAM-1 promotes steatohepatitis, β7-Integrin unexpectedly exerts protective effects. β7-/- mice show earlier steatohepatitis initiation and significantly stronger fibrosis progression. Accordingly, the interaction of β7-Integrins and their receptor MAdCAM-1 provide novel targets for therapeutic interventions in steatohepatitis. The mucosal addressin cell adhesion molecule 1 (MAdCAM-1) is expressed in livers upon diet-induced non-alcoholic steatohepatitis (NASH). Loss of MAdCAM-1 has beneficial effects regarding the development of NASH - manifested by reduced hepatic oxidative stress and decreased inflammation. In contrast, β7-Integrin-deficiency results in increased steatohepatitis.

Drescher HK ，Schippers A ，Clahsen T ，Sahin H ，Noels H ，Hornef M ，Wagner N ，Trautwein C ，Streetz KL ，Kroy DC ... -  《-》

Role of XBP1 in regulating the progression of non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is associated with the dysregulation of lipid metabolism and hepatic inflammation, though the underlying mechanisms remain unclear. We aimed to investigate the role of X-box binding protein-1 (XBP1) in the progression of NASH. Human liver tissues obtained from patients with NASH and controls were used to assess XBP1 expression. NASH models were developed in hepatocyte-specific Xbp1 knockout (Xbp1ΔHep), macrophage-specific Xbp1 knockout (Xbp1ΔMf), macrophage-specific Nlrp3 knockout, and wild-type (Xbp1FL/FL or Nlrp3FL/FL) mice fed with a high-fat diet for 26 weeks or a methionine/choline-deficient diet for 6 weeks. The expression of XBP1 was significantly upregulated in liver samples from patients with NASH. Hepatocyte-specific Xbp1 deficiency inhibited the development of steatohepatitis in mice fed the high-fat or methionine/choline-deficient diets. Meanwhile, macrophage-specific Xbp1 knockout mice developed less severe steatohepatitis and fibrosis than wild-type Xbp1FL/FL mice in response to the high-fat or methionine/choline-deficient diets. Macrophage-specific Xbp1 knockout mice showed M2 anti-inflammatory polarization. Xbp1-deleted macrophages reduced steatohepatitis by decreasing the expression of NLRP3 and secretion of pro-inflammatory cytokines, which mediate M2 macrophage polarization in macrophage-specific Xbp1 knockout mice. Steatohepatitis was less severe in macrophage-specific Nlrp3 knockout mice than in wild-type Nlrp3FL/FL mice. Xbp1-deleted macrophages prevented hepatic stellate cell activation by decreasing expression of TGF-β1. Less fibrotic changes were observed in macrophage-specific Xbp1 knockout mice than in wild-type Xbp1FL/FL mice. Inhibition of XBP1 suppressed the development of NASH. XBP1 regulates the development of NASH. XBP1 inhibitors protect against steatohepatitis. Thus, XBP1 is a potential target for the treatment of NASH. XBP1 is a transcription factor that is upregulated in liver tissues of patients with non-alcoholic steatohepatitis (NASH). Conditional knockout of Xbp1 in hepatocytes resulted in decreased lipid accumulation in mice, while genetic deletion of Xbp1 in macrophages ameliorated nutritional steatohepatitis and fibrosis in mice. Pharmacological inhibition of XBP1 protects against steatohepatitis and fibrosis, highlighting a promising therapeutic strategy for NASH.

Wang Q ，Zhou H ，Bu Q ，Wei S ，Li L ，Zhou J ，Zhou S ，Su W ，Liu M ，Liu Z ，Wang M ，Lu L ... -  《-》

Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice.

Gasdermin D (GSDMD)-executed programmed necrosis is involved in inflammation and controls interleukin (IL)-1β release. However, the role of GSDMD in non-alcoholic steatohepatitis (NASH) remains unclear. We investigated the role of GSDMD in the pathogenesis of steatohepatitis. Human liver tissues from patients with non-alcoholic fatty liver disease (NAFLD) and control individuals were obtained to evaluate GSDMD expression. Gsdmd knockout (Gsdmd-/-) mice, obese db/db mice and their wild-type (WT) littermates were fed with methionine-choline deficient (MCD) or control diet to induce steatohepatitis. The Gsdmd-/- and WT mice were also used in a high-fat diet (HFD)-induced NAFLD model. In addition, Alb-Cre mice were administered an adeno-associated virus (AAV) vector that expressed the gasdermin-N domain (AAV9-FLEX-GSDMD-N) and were fed with either MCD or control diet for 10 days. GSDMD and its pyroptosis-inducing fragment GSDMD-N were upregulated in liver tissues of human NAFLD/NASH. Importantly, hepatic GSDMD-N protein levels were significantly higher in human NASH and correlated with the NAFLD activity score and fibrosis. GSDMD-N remained a potential biomarker for the diagnosis of NASH. MCD-fed Gsdmd-/- mice exhibit decreased severity of steatosis and inflammation compared with WT littermates. GSDMD was associated with the secretion of pro-inflammatory cytokines (IL-1β, TNF-α, and MCP-1 [CCL2]) and persistent activation of the NF-ĸB signaling pathway. Gsdmd-/- mice showed lower steatosis, mainly because of reduced expression of the lipogenic gene Srebp1c (Srebf1) and upregulated expression of lipolytic genes, including Pparα, Aco [Klk15], Lcad [Acadl], Cyp4a10 and Cyp4a14. Alb-Cre mice administered with AAV9-FLEX-GSDMD-N showed significantly aggravated steatohepatitis when fed with MCD diet. As an executor of pyroptosis, GSDMD plays a key role in the pathogenesis of steatohepatitis, by controlling cytokine secretion, NF-ĸB activation, and lipogenesis. Non-alcoholic fatty liver disease has become one of the most feared chronic liver diseases, because it is the most rapidly growing indication for adult liver transplantation and a major cause of hepatocellular carcinoma. However, the mechanisms involved in the transformation of simple steatosis to steatohepatitis remain unclear. Herein, we show that gasdermin D driven pyroptosis is prominent in patients with non-alcoholic steatohepatitis (NASH), and gasdermin-N domain remains a potential biomarker for the diagnosis of NASH. Gasdermin D plays a key role in the pathogenesis of NASH by regulating lipogenesis, the inflammatory response, and the NF-ĸB signaling pathway, revealing potential treatment targets for NASH in humans.

Xu B ，Jiang M ，Chu Y ，Wang W ，Chen D ，Li X ，Zhang Z ，Zhang D ，Fan D ，Nie Y ，Shao F ，Wu K ，Liang J ... -  《-》