Littérature scientifique sur le sujet « Non Alcholic Steatohepatitis PDGF »

Liver fibrosis is considered: “a pathological repairing process in liver injuries leading to extracellular cell matrix (ECM) accumulation evidencing chronic liver diseases”. Chronic viral hepatitis, alcohol consumption, autoimmune diseases as well as non-alcoholic steatohepatitis are from the main causes of liver fibrosis (Lee et al., 2015; Mieli-Vergani et al., 2018). Hepatic stellate cells (HSCs) exist in the sinus space next to the hepatic epithelial cells as well as endothelial cells (Yin et al., 2013). Normally, HSCs are quiescent and mainly participate in fat storage and in the metabolism of vitamin A. HSCs are produced during liver injury and then transformed into myofibroblasts. The activated HSCs resulted in a sequence of events considered as marks fibrosis. The activation of HSCs mostly express alpha smooth muscle actin (α-SMA). Moreover, ECM is synthesized and secreted by HSCs that affects markedly the structure and function of the liver tissue leading to fibrosis (Tsuchida et al., 2017; Han et al., 2020). Hence, activated HSCs are attracting attention as potential targets in liver fibrosis. Many signaling molecules are involved in HSCs activation first and foremost, platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-β) (Tsuchida et al., 2017; Wang et al., 2020c) as interfering the PDGF or TGF-β signaling pathways is a growing field for liver fibrosis treatment.

Abstract Liver fibrosis marks the turning point of non-alcoholic steatohepatitis and with no specific and effective anti-fibrotic therapies available, this disease is a major global health burden. Here, we established the novel role of the Ron receptor in mitigating liver fibrosis. For 18 weeks, apolipoprotein E (ApoE KO) and ApoE x Ron double knockout (DKO) mice were fed a fat and cholesterol-rich diet. Livers from DKO animals exhibited increased accumulation of sirius red-stained collagen. Immunohistochemistry of αSMA revealed that DKO livers had increased activation of collagen-producing hepatic stellate cells. In agreement with this, DKO livers exhibited higher expression of pro-fibrogenic molecules, PDGF, CTGF, and TGFβ. Additionally, DKO mice exhibited increased hepatic expression of collagens (Types 1, 3, and 4) and ECM remodeling proteins (MMP-2 and TIMP-1). The expression of pro-fibrogenic inflammatory cytokines (TNFα and IL-12b), receptors (TLR-4), and chemokines (MIP-2, CCL2, and CCL5) were significantly higher in DKO livers. DKO livers also exhibited increased infiltration of F4/80+ Kupffer cells, which are well-known to mediate the majority of cytokine and chemokine expression in fibrotic livers. Ron also attenuated several risk factors of liver fibrosis including insulin resistance, steatosis, hepatocellular damage, and inflammation. Despite lifestyle changes and pharmacotherapies for treating etiologies of liver fibrosis, the disrupted liver homeostasis often remains and requires effective treatments. Investigating the protective functions of Ron offers a pharmacological target for resolving the steatohepatitis spectrum.

The prevalence of non-alcoholic steatohepatitis (NASH) is rapidly increasing and associated with cardiovascular disease (CVD), the major cause of mortality in NASH patients. Although sharing common risk factors, the mechanisms by which NASH may directly contribute to the development to CVD remain poorly understood. The aim of this study is to gain insight into key molecular processes of NASH that drive atherosclerosis development. Thereto, a time-course study was performed in Ldlr−/−.Leiden mice fed a high-fat diet to induce NASH and atherosclerosis. The effects on NASH and atherosclerosis were assessed and transcriptome analysis was performed. Ldlr−/−.Leiden mice developed obesity, hyperlipidemia and insulin resistance, with steatosis and hepatic inflammation preceding atherosclerosis development. Transcriptome analysis revealed a time-dependent increase in pathways related to NASH and fibrosis followed by an increase in pro-atherogenic processes in the aorta. Gene regulatory network analysis identified specific liver regulators related to lipid metabolism (SC5D, LCAT and HMGCR), inflammation (IL1A) and fibrosis (PDGF, COL3A1), linked to a set of aorta target genes related to vascular inflammation (TNFA) and atherosclerosis signaling (CCL2 and FDFT1). The present study reveals pathogenic liver processes that precede atherosclerosis development and identifies hepatic key regulators driving the atherogenic pathways and regulators in the aorta.

Abstract Non-alcoholic steatohepatitis (NASH) is quickly becoming the leading HCC etiology. NASH can lead to HCC by altering liver metabolism, inducing oncogenic mutations, causing tumor promoting inflammation as well as the immunosuppression of anti-HCC immunity. We have established an accurate model for studying NASH-induced HCC development, the MUP-uPA mouse, and used it to show that elevated TNF production by liver macrophages contributes to both NASH and HCC progression. The major cause of TNF induction during NASH is gut-derived endotoxin, whose infiltration into the portal circulation is enhanced by barrier disrupting diets that are high in fats or fructose. By disrupting autophagy and activating NF-kB, HFD feeding of MUP-uPA mice results in accumulation of p62, the major constituent of Mallory-Denk bodies, within hepatocytes. Accumulation of p62 is not required for induction of hepatosteatosis but it greatly accelerates and enhances NASH to HCC progression through the activation of NRF2 and mTORC1. Conditional activation of NRF2 in hepatocytes results in hepatomegaly due to induction of EGF and PDGF family members as well as altered liver metabolism, in part by triggering the degradation of fructose-1,6 bisphosphate phosphatase (FBP1). FBP1 is rate limiting for gluconeogenesis and its germ-line inherited deficiency results in a complex metabolic disorder that includes hypoglycemia, lactic acidosis, hepatomegaly, hepatosteatosis, hyperlipidemia and liver damage and is manifested only in response to glucose starvation. By generating Fbp1ΔHep mice, we found that FBP1 has enzymatic and non-enzymatic activities, the latter of which are due to formation of a multiprotein complex with aldolase B (ALDOB) and PP2A-C that interacts with AKT, dephosphorylates it and inhibits its activation. By inhibiting AKT activation, FBP1 and ALDOB suppress HCC development. Citation Format: Michael Karin, Li Gu, Yahui Zhu. Metabolic control of HCC initiation and progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA04.

AbstractVariability in disease development due to differences in strains and breeders constitutes a substantial challenge in preclinical research. However, the impact of the breeder on non-alcoholic steatohepatitis (NASH) is not yet fully elucidated. This retrospective study investigates NASH development in guinea pigs from Charles River or Envigo fed a high fat diet (20% fat, 15% sucrose, 0.35% cholesterol) for 16 or 24/25 weeks. Charles River animals displayed more severe NASH, with higher steatosis (p < 0.05 at week 16), inflammation (p < 0.05 at both week), fibrosis (p < 0.05 at week 16) and disease activity (p < 0.05 at both weeks). Accordingly, alanine and aspartate aminotransferase were increased at week 24/25 (p < 0.01). Hepatic expression of inflammatory (Ccl2, Cxcl8) and fibrotic (Pdgf, Serpine1, Col1a1) genes was also increased (p < 0.05). Differences were observed in healthy chow (4% fat, 0% sucrose, 0% cholesterol) fed animals: Envigo animals displayed higher relative liver weights (p < 0.01 at both weeks), liver cholesterol (p < 0.0001 at week 24/25) and aspartate aminotransferase (p < 0.05 at week 16), but lower levels of alkaline phosphatase (p < 0.0001 at week 24/25). These findings accentuates the importance of the breeder and its effect on NASH development and severity. Consequently, this may affect reproducibility, study comparison and limit the potential of developing novel therapies.

BACKGROUND AND AIMS: Congenital Hepatic Fibrosis (CHF) is caused by mutations in PKHD1, a gene encoding for fibrocystin, a protein of unknown function, expressed in cholangiocyte cilia and centromers. In CHF, biliary dysgenesis is accompanied by severe progressive portal fibrosis and portal hypertension. The mechanisms responsible for portal fibrosis in CHF are unclear. The αvβ6 integrin mediates local activation of TGFβ1 and is expressed by reactive cholangiocytes during cholestasis. To understand the mechanisms of fibrosis in CHF we studied the expression of αvβ6 integrin and its regulation in Pkhd1del4/del4 mice. METHODS: In Pkhd1del4/del4 mice we studied, at different ages (1-12 months): a) portal fibrosis (Sirius Red) and portal hypertension (spleen weight/body weight); b) αvβ6 mRNA and protein expression (RT-PCR, IHC); c) α-SMA and TGFβ1 mRNA expression (RT-PCR); d) portal inflammatory infiltrate (IHC for CD45 and FACS analysis of whole liver infiltrate); f) cytokines secretion from cultured monolayers of primary cholangiocytes (Luminex assay); g) cytokine effects on monocyte/macrophage proliferation (MTS assay) and migration (Boyden chamber); h) TGFβ1 and TNFα effects on β6 integrin mRNA expression by cultured cholangiocytes before and after inhibition of the TGFβ receptor type II (TGFβRII); i) TGFβ1 effects on collagen type I (COLL1) mRNA expression by cultured cholangiocytes. RESULTS: Pkhd1del4/del4 mice showed a progressive increase in αvβ6 integrin expression on biliary cyst epithelia. Expression of αvβ6 correlated with portal fibrosis (r=0.94, p<0.02) and with enrichment of a CD45+ve cell infiltrate in the portal space (r=0.97, p<0.01). Gene expression of TGFβ1 showed a similar age-dependent increase. FACS analysis showed that 50-75% of the CD45+ve cells were macrophages (CD45/CD11b/F4/80+ve). Cultured polarized Pkhd1del4/del4 cholangiocytes secreted from the basolateral side significantly increased amounts of CXCL1 and CXCL10 (p<0.05). Both cytokines were able to stimulate macrophage migration (p<0.05). Basal expression of β6 mRNA by cultured Pkhd1del4/del4 cholangiocytes (0.015±0.002 2^-dCt) was potently stimulated by the macrophage-derived cytokines TGFβ1 (0.017±0.002 2^-dCt, p<0.05) and TNFα (0.018±0.003 2^-dCt, p<0.05). Inhibition of TGFβRII completely blunted TGFβ1 (0.014±0.003 2^-dCt, p<0.05) but not TNFα effects (0.017±0.001 2^-dCt, p=ns) on β6 mRNA. COLL1 mRNA expression by cultured Pkhd1del4/del4 cholangiocytes (0.0009±0.0003 2^-dCt) was further and significantly increased after TGFβ1 stimulation (0.002±0.0005 2^-dCt, p<0.05). CONCLUSIONS: Pkhd1del4/del4 cholangiocytes possess increased basolateral secretory functions of chemokines (CXCL1, CXCL10) able to orchestrate macrophage homing to the peribiliary microenvironment. In turn, by releasing TGFβ1 and TNFα, macrophages up-regulate αvβ6 integrin in Pkhd1del4/del4 cholangiocytes. αvβ6 integrin activates latent TGFβ1, further increasing the fibrogenic properties of cholangiocytes.