Gene Expression

Hepatocyte nuclear factor 4 alpha (HNF4) is required for hepatocyte differentiation and regulates expression of genes involved in lipid and carbohydrate metabolism including those that control VLDL secretion and gluconeogenesis. Whereas previous studies have focused on specific genes regulated by HNF4 in metabolism, its overall role in whole-body energy utilization has not been studied. In this study, we used indirect calorimetry to determine the effect of hepatocyte-specific HNF4 deletion (HNF4-KO) in mice on whole-body energy expenditure (EE) and substrate utilization in fed, fasted, and high-fat diet (HFD) conditions...

Intramuscular administration of wild-type baculovirus is able to both protect against Plasmodium sporozoite challenge and eliminate liver-stage parasites via a Toll-like receptor 9-independent pathway. To investigate its effector mechanism(s), the gene expression profile in the liver of baculovirus-administered mice was characterized by cDNA microarray analysis. The ingenuity pathway analysis gene ontology module revealed that the major gene subsets induced by baculovirus were immune-related signaling, such as interferon signaling...

Genomic and transcriptomic analyses have well established that the major fraction of the mammalian genome is transcribed into different classes of RNAs ranging in size from a few nucleotides to hundreds of thousands of nucleotides, which do not encode any protein. Some of these non-coding RNAs (ncRNAs) are directly or indirectly linked to the regulation of expression or functions of ~25,000 proteins coded by <2% of the human genome. Among these regulatory RNAs, microRNAs are small (21-25 nucleotide) RNAs that are processed from precursor RNAs that have stem-loop structure, whereas non-coding RNAs >200 nucleotides are termed lncRNAs (long ncRNAs)...

Integrin Linked Kinase is a vital signaling protein ubiquitously expressed throughout the body. It binds to intracellular integrins to help promote signaling related to cell adhesion, apoptosis, proliferation, migration, and a plethora of other common cellular functions. In this review, ILK's role in the liver is detailed. Studies have shown ILK to be a major participant in hepatic ECM organization, liver regeneration, insulin resistance, and hepatocellular carcinoma.

The liver is uniquely bestowed with an ability to regenerate following a surgical or toxicant insult. One of the most researched models to demonstrate the regenerative potential of this organ is the partial hepatectomy model where two-thirds of the liver is surgically resected. The remnant liver replenishes the lost mass within 10-14 days in mice. The distinctive ability of the liver to regenerate has allowed living donor and split liver transplantation. One signaling pathway shown to be activated during the process of regeneration to contribute towards the mass and functional recovery of the liver is Wnt/β-catenin pathway...

Acetaminophen (APAP) hepatotoxicity is the most frequent cause of acute liver failure in the US. The mechanisms of APAP-induced liver injury have been under extensive investigations for decades and many key events of this necrotic cell death are known today. Initially, two opposing hypotheses for cell death were proposed: Reactive metabolite and protein adducts formation versus reactive oxygen and lipid peroxidation (LPO). In the end, both mechanisms were reconciled, and it is now generally accepted that the toxicity starts with formation of reactive metabolites which, after glutathione depletion, bind to cellular proteins, especially on mitochondria...

Biliary senescence and hepatic fibrosis are hallmarks of cholangiopathies including primary sclerosing cholangitis (PSC). Senescent cholangiocytes display senescence-associated secretory phenotypes [SASPs, e.g., transforming growth factor-1 (TGF-1)] that further increase biliary senescence (by an autocrine loop) and trigger liver fibrosis by paracrine mechanisms. The aim of this study was to determine the effect of p16 inhibition and role of the TGF-1/microRNA (miR)-34a/sirtuin 1 (SIRT1) axis in biliary damage and liver fibrosis in the Mdr2/ mouse model of PSC...

WNT/β-Catenin signaling promotes stemness, proliferation and cell fate decisions in various tissue stem cell compartments, which maintain organs with a high turnover of cells (e.g. skin, stomach and gut). Thus, the β-Catenin target genes AXIN2 and LGR5 are widely considered as tissue stem cell markers. In contrast, AXIN2 and LGR5 are expressed in pericentral hepatocytes, which do not show overt proliferation during liver homeostasis. Given the low hepatocyte turnover, the liver does not require constant high rates of proliferation, whereas WNT/β-Catenin signaling is critical for metabolic zonation...

Mast cells are key players in acute immune responses that are evidenced by degranulation leading to a heightened allergic response. Activation of mast cells can trigger a number of different pathways contributing to metabolic conditions and disease progression. Aging results in irreversible physiological changes affecting all organs, including the liver. The liver undergoes senescence, changes in protein expression and cell signaling phenotypes during aging, which regulates disease progression. Cellular senescence contributes to the age-related changes...

Globally, alcohol consumption contributes to more than 3 million deaths each year. While much of its ramifications is preventable, a coherent public health discourse on how to limit alcohol-related harms has been overdue. By synthesizing information from national and global databases, we show in this analysis that alcohol consumption level and alcohol-attributable burden of diseases, particularly alcoholic liver disease (ALD), are intimately linked to national income distribution, cultural norms, religion, sex, age, and health status...

Testing drugs in isogenic rodent strains to satisfy regulatory requirements is insufficient for derisking organ toxicity in genetically diverse human populations; in contrast, advances in mouse genetics can help mitigate these limitations. Compared to the expensive and slower in vivo testing, in vitro cultures enable the testing of large compound libraries toward prioritizing lead compounds and selecting an animal model with human-like response to a compound. In the case of the liver, a leading cause of drug attrition, isolated primary mouse hepatocytes (PMHs) rapidly decline in function within current culture platforms, which restricts their use for assessing the effects of longer-term compound exposure...

The Hippo pathway and its effector protein YAP (a transcriptional coactivator) have been identified as important in the biology of both hepatocellular carcinoma and cholangiocarcinoma. First identified as a tumor suppressor pathway in Drosophila , the understanding of the mammalian YAP signaling and its regulation continues to expand. In its "on" function, the canonical regulatory Hippo pathway, a well-described serine/threonine kinase module, regulates YAP function by restricting its subcellular localization to the cytoplasm...

The incidence of hepatocellular cancer (HCC) is gradually rising. HCC occurs as a sequela to various chronic liver diseases and ensuing cirrhosis. There have been many therapies approved for unresectable HCC in the last 5-years including immune checkpoint inhibitors and the overall response rates have improved. However, there are many cases which do not respond, and personalized medicine is lacking, making HCC an unmet clinical need. Generation of appropriate animal models have been key to our understanding of HCC...

Acetaminophen (APAP) overdose is the major cause of acute liver failure (ALF) in the Western world. Extensive research is ongoing to identify the mechanisms of APAP-induced ALF. APAP-induced acute liver injury is also one of the most commonly studied drug-induced liver injury models in the field of hepatotoxicity. APAP toxicity is triphasic and includes three mechanistically interlinked but temporally distinct phases of initiation, progression and recovery. Despite how commonly it is studied, the methods to study APAP toxicity differ significantly often leading to confusing and contradictory data...

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy worldwide and a leading cause of death worldwide. Its incidence continues to increase in the US due to hepatitis C infection and nonalcoholic steatohepatitis. Liver transplantation and resection remain the best therapeutic options for a cure, but these are limited by the shortage of available organs for transplantation, diagnosis at an advanced stage, and underlying chronic liver disease found in most patients with HCC. Immune checkpoint inhibitors (ICIs) have been shown to be an evolving novel treatment option in certain advanced solid tumors and have been recently approved for inoperable, advanced and metastatic HCC...

BACKGROUND: Liver progenitor cells (LPCs) contribute to liver regeneration during chronic damage and are implicated as cells of origin for liver cancers including hepatocellular carcinoma (HCC). The CDKN2A locus, which encodes the tumour suppressors ARF and INK4A, was identified as one of the most frequently altered genes in HCC. This study demonstrates that inactivation of Cdkn2a enhances tumorigenic transformation of LPCs. METHODS: The level of ARF and INK4A expression was determined in a panel of transformed and non-transformed wild-type LPC lines...

Human liver models that are 3-dimensional (3D) in architecture are indispensable for compound metabolism/toxicity screening, to model liver diseases for drug discovery, and for cell-based therapies; however, further development of such models is needed to maintain high levels of primary human hepatocyte (PHH) functions for weeks to months. Therefore, here we determined how microscale 3D collagen-I presentation and fibroblast interaction affects the longevity of PHHs. High-throughput droplet microfluidics was utilized to generate reproducibly-sized (~300 µm diameter) microtissues containing PHHs encapsulated in collagen-I +/- supportive fibroblasts, namely 3T3-J2 murine embryonic fibroblasts or primary human hepatic stellate cells (HSCs); self-assembled spheroids and bulk collagen gels (macrogels) containing PHHs served as controls...

Hepatic stellate cells (HSC) are critical effector cells of liver fibrosis. In the injured liver, HSC differentiate into a myofibrobastic phenotype. A critical feature distinguishing myofibroblastic from quiescent HSC is cytoskeletal reorganization. Soluble-NSF-attachment receptor (SNARE) proteins are important in trafficking of newly synthesized proteins to the plasma membrane for release into the extracellular environment. The goals of this project were to determine the expression of specific SNARE proteins in myofibroblastic HSC and to test whether their alteration changed HSC phenotype in vitro and progression of liver fibrosis in vivo...

Cholangiopathies are chronic, progressive diseases of the biliary tree, and can be either acquired or genetic. The primary target is the cholangiocyte (CC), the cell type lining the bile duct that is responsible for bile modification and transport. Despite advances in our understanding and diagnosis of these diseases in recent years, there are no proven therapeutic treatments for the majority of the cholangiopathies, and liver transplantation is the only life-extending treatment option for patients with end-stage cholestatic liver disease...

Testing drugs in isogenic rodent strains to satisfy regulatory requirements is insufficient for derisking organ toxicity in genetically diverse human populations; in contrast, advances in mouse genetics can help mitigate these limitations. Compared to the expensive and slower in vivo testing, in vitro cultures enable the testing of large compound libraries towards prioritizing lead compounds and selecting an animal model with human-like response to a compound. In the case of the liver, a leading cause of drug attrition, isolated primary mouse hepatocytes (PMHs) rapidly decline in function within current culture platforms, which restricts their use for assessing the effects of longer-term compound exposure...