Mechanisms of liver injury in high fat sugar diet fed mice that lack hepatocyte X-box binding protein 1.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of liver diseases in the United States and can progress to cirrhosis, end-stage liver disease and need for liver transplantation. There are limited therapies for NAFLD, in part, due to incomplete understanding of the disease pathogenesis, which involves different cell populations in the liver. Endoplasmic reticulum stress and its adaptative unfolded protein response (UPR) signaling pathway have been implicated in the progression from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH).

Farnesoid X receptor signaling activates the hepatic X-box binding protein 1 pathway in vitro and in mice.

Unlabelled: Bile acids are endogenous ligands of the nuclear receptor, farnesoid X receptor (FXR), and pharmacological FXR modulators are under development for the treatment of several liver disorders. The inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) pathway of the unfolded protein response (UPR) is a protective cellular signaling pathway activated in response to endoplasmic reticulum (ER) stress. We investigated the role of FXR signaling in activation of the hepatic XBP1 pathway.

Hepatic deletion of X-box binding protein 1 impairs bile acid metabolism in mice.

The unfolded protein response (UPR) is an adaptive response to endoplasmic reticulum stress and the inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) pathway of the UPR is important in lipid metabolism. However, its role in bile acid metabolism remains unknown. We demonstrate that liver-specific knockout (LS-) mice had a 45% reduction in total bile acid pool.

Epidermal growth factor inhibits transforming growth factor-β-induced fibrogenic differentiation marker expression through ERK activation.

Transforming growth factor-β (TGF-β) signaling plays an important and complex role in renal fibrogenesis. The seemingly simple TGF-β/Smad cascade is intensively regulated at several levels, including crosstalk with other signaling pathways. Epidermal growth factor (EGF) is a potent mitogen for epithelial cells and is elevated in diseased kidneys.

Hypoxia-inducible factor-2α and TGF-β signaling interact to promote normoxic glomerular fibrogenesis.

Hypoxia-inducible factors (HIFs) are transcription factors consisting of an oxygen-sensitive α-subunit binding to a stable β-subunit. HIFs regulate multiple signaling pathways that could contribute to fibrogenesis, supporting their potential role in hypoxia-mediated renal fibrosis. We previously reported that HIF-1 is upregulated and required for transforming growth factor (TGF)-β induction of collagen in renal tubular cells.

TGF-β/Smad3 activates mammalian target of rapamycin complex-1 to promote collagen production by increasing HIF-1α expression.

Transforming growth factor (TGF)-β is a major mediator of kidney fibrosis. In the past decade it was recognized that, besides canonical Smad signaling, many other signaling pathways participate in the process of TGF-β-induced fibrogenesis. One such pathway involves mammalian target of rapamycin complex (mTORC)1.

A conceptual framework for the molecular pathogenesis of progressive kidney disease.

The data regarding the pathogenesis of progressive kidney disease implicate cytokine effects, physiological factors, and myriad examples of relatively nonspecific cellular dysfunction. The sheer volume of information being generated on this topic threatens to overwhelm our efforts to understand progression in chronic kidney disease or to derive rational strategies to treat it. Here, a conceptual framework is offered for organizing and considering these data.

Rac1 promotes TGF-beta-stimulated mesangial cell type I collagen expression through a PI3K/Akt-dependent mechanism.

Transforming growth factor (TGF)-beta is a central mediator in the progression of glomerulosclerosis, leading to accumulation of aberrant extracellular matrix proteins and inappropriate expression of smooth muscle alpha-actin in the kidney. Previously, we reported that disrupting the cytoskeleton diminished TGF-beta-stimulated type I collagen accumulation in human mesangial cells. As cytoskeletal signaling molecules, including the Rho-family GTPases, have been implicated in fibrogenesis, we sought to determine the respective roles of RhoA and Rac1 in HMC collagen I expression.

TGF-beta signal transduction in chronic kidney disease.

Transforming growth factor (TGF)-beta is a central stimulus of the events leading to chronic progressive kidney disease, having been implicated in the regulation of cell proliferation, hypertrophy, apoptosis and fibrogenesis. The fact that it mediates these varied events suggests that multiple mechanisms play a role in determining the outcome of TGF-beta signaling. Regulation begins with the availability and activation of TGF-beta and continues through receptor expression and localization, control of the TGF-beta family-specific Smad signaling proteins, and interaction of the Smads with multiple signaling pathways extending into the nucleus.

Cytoskeletal rearrangement and signal transduction in TGF-beta1-stimulated mesangial cell collagen accumulation.

TGF-beta1 has been implicated in glomerular extracellular matrix accumulation, although the precise cellular mechanism(s) by which this occurs is not fully understood. The authors have previously shown that the Smad signaling pathway is present and functional in human glomerular mesangial cells and plays a role in activating type I collagen gene expression. It also was determined that TGF-beta1 activates ERK mitogen-activated protein kinase in mesangial cells to enhance Smad activation and collagen expression.

TGF-beta signal transduction and mesangial cell fibrogenesis.

Transforming growth factor-beta (TGF-beta) is closely associated with progressive renal fibrosis. Significant progress has been accomplished in determining the cellular signaling pathways that are activated by TGF-beta. This knowledge is being applied to glomerular mesangial cell models of extracellular matrix (ECM) accumulation.