Association of Differentially Altered Liver Fibrosis with Deposition of TGFBi in Stabilin-Deficient Mice

Abstract

Liver sinusoidal endothelial cells (LSECs) control clearance of Transforming growth factor, beta-induced, 68kDa (TGFBi) and Periostin (POSTN) through scavenger receptors Stabilin-1 (Stab1) and Stabilin-2 (Stab2). Stabilin inhibition can ameliorate atherosclerosis in mouse models, while Stabilin-double-knockout leads to glomerulofibrosis. Fibrotic organ damage may pose a limiting factor in future anti-Stabilin therapies. While Stab1-deficient (Stab1−/−) mice were shown to exhibit higher liver fibrosis levels upon challenges, fibrosis susceptibility has not been studied in Stab2-deficient (Stab2−/−) mice. Wildtype (WT), Stab1−/− and Stab2−/− mice were fed experimental diets, and local ligand abundance, hepatic fibrosis, and ligand plasma levels were measured. Hepatic fibrosis was increased in both Stab1−/− and Stab2−/− at baseline. A pro-fibrotic short Methionine-Choline-deficient (MCD) diet induced slightly increased liver fibrosis in Stab1−/− and Stab2−/− mice. A Choline-deficient L-amino acid-defined (CDAA) diet induced liver fibrosis of similar distribution and extent in all genotypes (WT, Stab1−/− and Stab2−/−). A hepatic abundance of Stabilin ligand TGFBi correlated very highly with liver fibrosis levels. In contrast, plasma levels of TGFBi were increased only in Stab2−/− mice after the CDAA diet but not the MCD diet, indicating the differential effects of these diets. Here we show that a single Stabilin deficiency of either Stab1 or Stab2 induces mildly increased collagen depositions under homeostatic conditions. Upon experimental dietary challenge, the local abundance of Stabilin ligand TGFBi was differentially altered in Stabilin-deficient mice, indicating differentially affected LSEC scavenger functions. Since anti-Stabilin-directed therapies are in clinical evaluation for the treatment of diseases, these findings bear relevance to treatment with novel anti-Stabilin agents.

TGFBI promotes proliferation and epithelial–mesenchymal transition in renal cell carcinoma through PI3K/AKT/mTOR/HIF-1α pathway

“…TGFBI plays a key role in the activation of PI3K/AKT/mTOR/ HIF-1α signaling pathway in RCC Previous literature has reported a close relationship between POSTN and TGFBI [19][20][21][22], We analyzed the correlation between TGFBI and POSTN at RNA, total protein, and phosphoprotein levels and found a positive correlation between the expression of the two (Fig. 6A), whereas previous studies have been performed on POSTN indicating the importance of the AKT/mTOR pathway in RCC [23] .…”

Deficiency of Stabilin-1 in the Context of Hepatic Melanoma Metastasis

“…Healthy, untreated mice showed significantly higher levels of TGFBI (p = 0.0159) and POSTN (p = 0.0079) upon loss of Stab1 as compared to Ctrl. In disease processes such as liver fibrosis or arteriosclerosis, reduced clearance functions by loss of Stab1 are further exaggerated [10,33]. Levels of TGFBI in the liver correlate with the intensity of perisinusoidal fibrosis in Stab1 KO [33].…”

“…In disease processes such as liver fibrosis or arteriosclerosis, reduced clearance functions by loss of Stab1 are further exaggerated [10,33]. Levels of TGFBI in the liver correlate with the intensity of perisinusoidal fibrosis in Stab1 KO [33]. In cancer, stromal expression of POSTN is a predictor of poorer survival in CRC [34].…”

Insights into Hepatocellular Carcinoma: From Pathophysiology to Novel Therapies

“…Moreover, after an experimental dietary challenge, the hepatic content of the Stabilin ligand TGFBi is differently altered in Stabilin-deficient mice, suggesting that the scavenger functions of LSECs are differentially affected in these mice. These findings suggest the evaluation of anti-Stabilin therapies, which are currently undergoing clinical evaluation for other diseases, for the improvement of hepatic fibrosis [3].…”