Nonalcoholic fatty liver disease consists of a range of disorders characterized by excess accumulation of triglyceride within the liver. Whereas simple steatosis is clinically benign, nonalcoholic ...steatohepatitis (NASH) often progresses to cirrhosis. Inflammation and fibrogenesis are closely inter-related and are major targets of NASH research. Experimental data have shown that inflammation in NASH is caused by insulin resistance, systemic lipotoxicity due to overnutrition, lipid metabolites, the production of proinflammatory cytokines and adipokines by visceral adipose tissue, gut-derived bacteria, and oxidative stress. In NASH-associated fibrosis, the principal cell type responsible for extracellular matrix production is recognized as the hepatic stellate cell. Although the fibrotic mechanisms underlying NASH are largely similar to those observed in other chronic liver diseases, the altered patterns of circulating adipokines, the generation of oxidative stress, and the hormonal profile associated with the metabolic syndrome might play unique roles in the fibrogenesis associated with the disease. Information on the basic pathogenesis of NASH with a focus on the generation of inflammation and fibrosis will be discussed.
The gut and the liver are anatomically and physiologically connected, and this “gut–liver axis” exerts various influences on liver pathology. The gut microbiota consists of various microorganisms ...that normally coexist in the human gut and have a role of maintaining the homeostasis of the host. However, once homeostasis is disturbed, metabolites and components derived from the gut microbiota translocate to the liver and induce pathologic effects in the liver. In this review, we introduce and discuss the mechanisms of liver inflammation, fibrosis, and cancer that are influenced by gut microbial components and metabolites; we include recent advances in molecular‐based therapeutics and novel mechanistic findings associated with the gut–liver axis and gut microbiota.
In the situation of leaky gut, a large amount of gut microbial components and metabolites are transferred to the liver and are likely to promote liver cancer progression. Hepatocellular carcinomas (HCCs) in the cirrhotic liver were associated with continuous exposure of lipopolysaccharide (LPS) from gram‐negative bacteria of the gut microbiota. The development of NASH/NAFLD is also associated with LPS exposure.
Nonalcoholic fatty liver disease (NAFLD) consists of the entire spectrum of fatty liver disease in patients without significant alcohol consumption, ranging from nonalcoholic fatty liver (NAFL) to ...nonalcoholic steatohepatitis (NASH) to cirrhosis, with NASH recently shown as an important cause of hepatocellular carcinoma (HCC). There is a close relationship between insulin resistance (IR) and NAFLD, with a five-fold higher prevalence of NAFLD in patients with type 2 diabetes (T2DM) compared to that in patients without T2DM. IR is involved in the progression of disease conditions such as steatosis and NASH, as well as hepatic fibrosis progression. The mechanisms underlying these processes involve genetic factors, hepatic fat accumulation, alterations in energy metabolism, and inflammatory signals derived from various cell types including immune cells. In NASH-associated fibrosis, the principal cell type responsible for extracellular matrix production is the hepatic stellate cell (HSC). HSC activation by IR involves "direct" and "indirect" pathways. This review will describe the molecular mechanisms of inflammation and hepatic fibrosis in IR, the relationship between T2DM and hepatic fibrosis, and the relationship between T2DM and HCC in patients with NAFLD.
MicroRNAs in hepatic pathophysiology Murakami, Yoshiki; Kawada, Norifumi
Hepatology research,
January 2017, Volume:
47, Issue:
1
Journal Article
Peer reviewed
Open access
MicroRNAs (miRNAs) are a group of small non‐coding RNAs that range in length from 20 to 25 nucleotides. MicroRNAs are specific for multiple cellular functions, including cell generation, ...differentiation, multiplication, carcinogenesis, and apoptosis. Many researchers have recently reported that the aberrant expression of miRNAs in hepatic tissue was related to the pathogenesis of liver disease, including viral hepatitis, hepatocellular carcinoma, and fatty liver disease. Multiple studies have proposed that an analysis of circulating miRNAs may be useful for diagnosing etiologies or staging the progression of liver disease, as well as for therapeutic purposes, for example, nucleic acid therapy. This review summarizes and discusses recent advances in the knowledge of miRNAs for chronic liver diseases, with special interest in viral hepatitis, liver fibrosis, and biomarkers.
Molecular analysis of hepatic fibrogenesis has progressed with respect to both fibrosis progression and regression by using cell biological, molecular biological and (epi)genetic approaches. Recent ...researches have revealed sources of collagen‐producing cells other than hepatic stellate cells in the liver, and the involvement of the innate immune system and oxidative stress in the fibrotic process has attracted new attention. Together with these advancements in basic knowledge on the cellular and molecular biology of hepatic fibrosis, clinical researches have linked the clarification of the relationship between progression of the fibrosis stage and therapeutic efficacy for chronic viral hepatitis and non‐alcoholic steatohepatitis and validation of the regression of advanced fibrosis, even cirrhosis, of appropriate therapies using modern medicines. Furthermore, non‐invasive assessment of liver fibrosis using an ultrasound‐based modality has become a focus in the clinical diagnosis of liver fibrosis instead of liver biopsy. Taken together, liver fibrosis research has been evolving both basically and clinically in the past three decades.
In chronic liver disease, hepatic stellate cell activation and degeneration of liver sinusoidal endothelial cells lead to structural changes, which are secondary to fibrosis and the presence of ...regenerative nodules in the sinusoids, and to functional changes, which are related to vasoconstriction. The combination of such changes increases intrahepatic vascular resistance and causes portal hypertension. The subsequent increase in splanchnic and systemic hyperdynamic circulation further increases the portal blood flow, thereby exacerbating portal hypertension. In clinical practice, the hepatic venous pressure gradient is the gold-standard measure of portal hypertension; a value of ≥10 mm Hg is defined as clinically significant portal hypertension, which is severe and is associated with the risk of liver-related events. Hepatic venous pressure gradient measurement is somewhat invasive, so evidence on the utility of risk stratification by elastography and serum biomarkers is needed. The various stages of cirrhosis are associated with different outcomes. In viral hepatitis-related cirrhosis, viral suppression or elimination by nucleos(t)ide analog or direct-acting antivirals results in recompensation of liver function and portal pressure. However, careful follow-up should be continued, because some cases have residual clinically significant portal hypertension even after achieving sustained virologic response. In this study, we reviewed the current and future prospects for portal hypertension.
MicroRNAs (miRNAs) are important in hepatic pathophysiology and the development of liver cancer.
To explore miRNAs that are regulated with the progression of liver fibrosis caused by chronic liver ...disease.
The regulated miRNAs in human livers infected with hepatitis C virus were identified by microarray analysis. Their expression in human livers with non-alcoholic steatohepatitis, mouse livers from two fibrosis models and cultured stellate cells was validated by real-time RT-PCR. The regulation of miR-222 expression in stellate cells by nuclear factor kappa B (NF-κB) was assayed. Finally, the effects of an miR-222 precursor or inhibitor on the expression of cyclin-dependent kinase inhibitor 1B (CDKN1B) and the growth of LX-2 cells were determined.
It was found that miR-199a-5p/199a-3p and miR-221/222 were upregulated in the human liver in a fibrosis progression-dependent manner. Among these miRNAs, miR-221/222 were upregulated in LX-2 cells and increased during the course of culture-dependent activation of mouse primary stellate cells, in a manner similar to the expression of α1(I) collagen and α-smooth muscle actin mRNAs. The expression of miR-221/222 increased in mouse models of liver fibrosis. In contrast, an NF-κB inhibitor significantly suppressed the miR-222 induction that was stimulated in culture by transforming growth factor α or tumour necrosis factor α. Although overexpression or downregulation of miR-222 failed to regulate the growth of LX-2 cells, miR-222 bound to the CDKN1B 3'UTR and regulated the expression of the corresponding protein.
miR-221/222 may be new markers for stellate cell activation and liver fibrosis progression.
Liver cancer ranks sixth in cancer incidence,and is the third leading cause of cancer-related deaths worldwide.Hepatocellular carcinoma(HCC)is the most common type of liver cancer,which arises from ...hepatocytes and accounts for approximately 70%-85%of cases.Hepatitis B virus(HBV)frequently causes liver inflammation,hepatic damage and subsequent cirrhosis.Integrated viral DNA is found in 85%-90%of HBV-related HCCs.Its presence in tumors from non-cirrhotic livers of children or young adults further supports the role of viral DNA integration in hepatocarcinogenesis.Integration of subgenomic HBV DNA fragments into different locations within the host DNA is a significant feature of chronic HBV infection.Integration has two potential consequences:(1)the host genome becomes altered("cis"effect);and(2)the HBV genome becomes altered("trans"effect).The cis effect includes insertional mutagenesis,which can potentially disrupt host gene function or alter host gene regulation.Tumor progression is frequently associated with rearrangement and partial gain or loss of both viral and host sequences.However,the role of integrated HBV DNA in hepatocarcinogenesis remains controversial.Modern technology has provided a new paradigm to further our understanding ofdisease mechanisms.This review summarizes the role of HBV DNA integration in human carcinogenesis.
The identity of the specific nitric oxide dioxygenase (NOD) that serves as the main in vivo regulator of O
-dependent NO degradation in smooth muscle remains elusive. Cytoglobin (Cygb) is a recently ...discovered globin expressed in fibroblasts and smooth muscle cells with unknown function. Cygb, coupled with a cellular reducing system, efficiently regulates the rate of NO consumption by metabolizing NO in an O
-dependent manner with decreased NO consumption in physiological hypoxia. Here we show that Cygb is a major regulator of NO degradation and cardiovascular tone. Knockout of Cygb greatly prolongs NO decay, increases vascular relaxation, and lowers blood pressure and systemic vascular resistance. We further demonstrate that downregulation of Cygb prevents angiotensin-mediated hypertension. Thus, Cygb has a critical role in the regulation of vascular tone and disease. We suggest that modulation of the expression and NOD activity of Cygb represents a strategy for the treatment of cardiovascular disease.
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