Livers, Volume 1, Issue 3 (September 2021) – 5 articles

Antifibrotic therapies for the treatment of liver fibrosis represent an unconquered area of drug development. The significant involvement of the gut microbiota as a driving force in a multitude of liver disease, be it pathogenesis or fibrotic progression, suggest that targeting the gut–liver axis, relevant signaling pathways, and/or manipulation of the gut’s commensal microbial composition and its metabolites may offer opportunities for biomarker discovery, novel therapies and personalized medicine development. Here, we review potential links between bacterial translocation and deficits of host-microbiome compartmentalization and liver fibrosis that occur in settings of advanced chronic liver disease. We discuss established and emerging therapeutic strategies, translated from our current knowledge of the gut–liver axis, targeted at restoring intestinal eubiosis, ameliorating hepatic fibrosis and rising portal hypertension that characterize and define the course of decompensated cirrhosis. Full article

Liver cancer is estimated to be the fifth most common in the world, while it is also considered the third leading cause of cancer death. In cases of primary liver cancer, surgery in combination with chemotherapy and radiotherapy can lead to a complete cure or significantly increase the patient’s life expectancy. Since the liver is an organ that performs several critical functions in the human body, the precise estimation of the disease (position and size of tumors and its vicinity to vessels) plays a vital role in a successful operation. In some cases, the removal of the tumor may be successful, but the percentage of the hepatic remnant may not be sufficient to sustain life. Therefore, accurate imaging of the tumor of the liver and proper planning of a difficult surgery to remove tumor(s) from a patient’s liver can be a lifesaver and lead to a complete cure of the disease. The aim of the present study is the initial accurate representation of the liver (parenchyma, tumors, vessels) as a digital three-dimensional (3D) model using advanced image processing and machine learning techniques and its 3D printing in 1:1 scale representing the full size of the liver with the tumor(s). A model of this type has been used at our University surgical department to plan complex hepatobiliary surgeries, provide more accurate information to the patients and their families, as well as improve the training of medical students and resident surgeons and fellows. Full article

Rare liver diseases caused by ductal plate malformation, such as congenital hepatic fibrosis (CHF), Caroli syndrome, and polycystic liver disease, can have clinical manifestations such as recurrent cholangitis—frequently involving multidrug-resistant microorganisms—leading to difficulties in selecting the optimal antimicrobial treatment. Without prompt recognition, these infections severely hamper the patient’s quality of life and can develop into life-threatening complications. We report here the case of a 50-year-old woman with a history of recurring cholangitis with occasional systemic involvement leading to bloodstream infection, who ultimately received a diagnosis of CHF and was put on chronic suppressive antibiotic therapy while on the waiting list for a liver transplant. We also reviewed the literature collecting cases of recurrent infections occurring in patients with ductal plate malformation. Full article

Hepatic steatosis is a consequence of distorted lipid storage and plays a vital role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). This study aimed to explore the role of the COP9 signalosome (CSN) in the development of hepatic steatosis and its interplay with the deubiquitylating enzyme (DUB) cylindromatosis (CYLD). CSN occurs as CSN^CSN7A and CSN^CSN7B variants regulating the ubiquitin proteasome system. It is a deneddylating complex and associates with other DUBs. CYLD cleaves Lys63-ubiquitin chains, regulating a signal cascade that mitigates hepatic steatosis. CSN subunits CSN1 and CSN7B, as well as CYLD, were downregulated with specific siRNA in HepG2 cells and human primary hepatocytes. The same cells were transfected with Flag-CSN7A or Flag-CSN7B for pulldowns. Hepatic steatosis in cell culture was induced by palmitic acid (PA). Downregulation of CSN subunits led to reduced PPAR-γ expression. Flag-pulldowns in both LiSa-2 and HepG2 cells and human primary hepatocytes revealed binding of CYLD preferentially to CSN^CSN7A. This was influenced by PA treatment. Silencing of CSN^CSN7B blocked lipid droplet formation caused a compensatory increase of CSN^CSN7A stabilizing CYLD. Our results demonstrate that CSN^CSN7A-mediated CYLD stabilization impedes hepatic steatosis. Therefore, stabilizing CSN^CSN7A-CYLD interaction might be a strategy to retard hepatic steatosis. Full article

Mitochondria have been studied for decades from the standpoint of metabolism and ATP generation. However, in recent years mitochondrial dynamics and its influence on bioenergetics and cellular homeostasis is also being appreciated. Mitochondria undergo regular cycles of fusion and fission regulated by various cues including cellular energy requirements and pathophysiological stimuli, and the network of critical proteins and membrane lipids involved in mitochondrial dynamics is being revealed. Hepatocytes are highly metabolic cells which have abundant mitochondria suggesting a biologically relevant role for mitochondrial dynamics in hepatocyte injury and recovery. Here we review information on molecular mediators of mitochondrial dynamics and their alteration in drug-induced liver injury. Based on current information, it is evident that changes in mitochondrial fusion and fission are hallmarks of liver pathophysiology ranging from acetaminophen-induced or cholestatic liver injury to chronic liver diseases. These alterations in mitochondrial dynamics influence multiple related mitochondrial responses such as mitophagy and mitochondrial biogenesis, which are important adaptive responses facilitating liver recovery in several contexts, including drug-induced liver injury. The current focus on characterization of molecular mechanisms of mitochondrial dynamics is of immense relevance to liver pathophysiology and have the potential to provide significant insight into mechanisms of liver recovery and regeneration after injury. Full article