Metabolic Reprogramming of Liver Fibrosis

Abstract

Liver fibrosis is an excessive and imbalanced deposition of fibrous extracellular matrix (ECM) that is associated with the hepatic wound-healing response. It is also the common mechanism that contributes to the impairment of the liver function that is observed in many chronic liver diseases (CLD). Despite the efforts, no effective therapy against fibrosis exists yet. Worryingly, due to the growing obesity pandemic, fibrosis incidence is on the rise. Here, we aim to summarize the main components and mechanisms involved in the progression of liver fibrosis, with special focus on the metabolic regulation of key effectors of fibrogenesis, hepatic stellate cells (HSCs), and their role in the disease progression. Hepatic cells that undergo metabolic reprogramming require a tightly controlled, fine-tuned cellular response, allowing them to meet their energetic demands without affecting cellular integrity. Here, we aim to discuss the role of ribonucleic acid (RNA)-binding proteins (RBPs), whose dynamic nature being context- and stimuli-dependent make them very suitable for the fibrotic situation. Thus, we will not only summarize the up-to-date literature on the metabolic regulation of HSCs in liver fibrosis, but also on the RBP-dependent post-transcriptional regulation of this metabolic switch that results in such important consequences for the progression of fibrosis and CLD.

Liver Fibrosis in Primary Sjögren’s Syndrome

“…The fact that pSS affects liver frequently implies shared epitopes or epitope spreading across epithelial structures and particularly among salivary epithelium, biliary epithelium, and/or hepatocytes ( 27 ). In this case, a clinically silent chronic inflammatory process may evolve into liver parenchyma leading to LF ( 36 – 38 ). Fibrogenesis may be further promoted by several comorbidities or drugs, and therefore, it is reasonable to assume that LF might occur in higher prevalence among pSS patients compared to the general population.…”

RNA-binding proteins in metabolic-associated fatty liver disease (MAFLD): From mechanism to therapy

“…CUGBP1 specifically binds to interferon (IFN)-γ mRNA and promotes the transforming growth factor (TGF)-β signal pathway, thereby promoting the activation of HSCs, which ultimately leads to the occurrence of fibrosis and liver cirrhosis (118). CPEB4, a member of the CPEB family, is highly expressed in the liver and has also been found to prevent HSCs activation and liver fibrosis by silencing (119). In the early stage of HSC activation, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3(PFKFB3) protein is continuously upregulated by CPEB4 and its binding RNA, which has become a potential target for anti-fibrosis and prevention of liver cirrhosis (120).…”

Special Issue on “Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis II”

“…The review of Delgado et al shed light on the biology of hepatic stellate cells (HSCs) that are in the disease liver the major cellular contributors to excess ECM deposition. In special focus of this contribution are ribonucleic acid (RNA)-binding proteins and other RNA-regulators that significantly contribute to the activation and metabolic reprogramming of HSCs during progression of hepatic fibrogenesis [ 6 ]. This article illustrates that the activity of these molecular factors is highly dynamic, and subtle disturbances in their proper regulation result in dysregulated protein expression and altered functions impacting the general process of fibrogenesis.…”