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.
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.
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases worldwide, including in Japan. The Japanese Society of Gastroenterology (JSGE) and the Japanese Society of ...Hepatology (JSH) have established the Japanese NAFLD/NASH guidelines in 2014 and revised these guidelines in 2020. As described in these guidelines, weight reduction by diet and/or exercise therapy is important for the treatment of NAFLD patients. The I148M single nucleotide polymorphism (rs738409 C > G) of
PNPLA3
(patatin-like phospholipase domain-containing 3 protein) is widely known to be associated with the occurrence and progression of NAFLD. In the Japanese, the ratio of
PNPLA3
gene polymorphisms found is approximately 20%, which is higher than that found in Westerners. In addition, the ratio of lean NAFLD patients is also higher in Japan than in Western countries. Therefore, the method for lifestyle guidance for the NAFLD patients in Japan would be different from that for the people in Western countries. The problems in the treatment of NAFLD patients include alcohol consumption and sarcopenia. Therefore, guidelines that can help clinicians treat Japanese patients with NAFLD are needed. In this expert review, we summarize evidence-based interventions for lifestyle modification (diet, exercise, alcohol, and sarcopenia) for the treatment of patients with NAFLD, especially from Japan and Asian countries.
Although parathyroid hormone is known to be related with calcium and phosphate metabolism, it has been also reported to have several effects on the cardiovascular system including heart and vessels. ...However, the detailed pathophysiological mechanisms remain unclear. Clinical studies have indicated that parathyroid hormone is associated with cardiovascular events and mortality not only in patients with chronic kidney disease but also in those without chronic kidney disease. As a possible mechanism, it is thought that parathyroid hormone is associated with the renin‐angiotensin‐aldosterone system and has direct effects on the cardiovascular system. Therefore, we should pay attention to not only the control of serum phosphate and calcium levels but also the control of serum parathyroid hormone levels, especially in patients with chronic kidney disease.
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.
In patients on maintenance dialysis, cardiovascular mortality risk is remarkably high, which can be partly explained by severe coronary artery calcification (CAC). Hyperphosphatemia has been reported ...to be associated with the severity of CAC. However, the optimal phosphate range in patients on dialysis remains unknown. This study was planned to compare the effects on CAC progression of two types of noncalcium-based phosphate binders and of two different phosphate target ranges.
We conducted a randomized, open-label, multicenter, interventional trial with a two by two factorial design. A total of 160 adults on dialysis were enrolled and randomized to the sucroferric oxyhydroxide or lanthanum carbonate group, with the aim of reducing serum phosphate to two target levels (3.5-4.5 mg/dl in the strict group and 5.0-6.0 mg/dl in the standard group). The primary end point was percentage change in CAC scores during the 12-month treatment.
The full analysis set included 115 patients. We observed no significant difference in percentage change in CAC scores between the lanthanum carbonate group and the sucroferric oxyhydroxide group. On the other hand, percentage change in CAC scores in the strict group (median of 8.52; interquartile range, -1.0-23.9) was significantly lower than that in the standard group (median of 21.8; interquartile range, 10.0-36.1;
=0.006). This effect was pronounced in older (aged 65-74 years) versus younger (aged 20-64 years) participants (
value for interaction =0.003). We observed a similar finding for the absolute change in CAC scores.
Further study with a larger sample size is needed, but strict phosphate control shows promise for delaying progression of CAC in patients undergoing maintenance hemodialysis.
Evaluate the New Phosphate Iron-Based Binder Sucroferric Oxyhydroxide in Dialysis Patients with the Goal of Advancing the Practice of EBM (EPISODE), jRCTs051180048.
Fibroblast growth factor (FGF) 21 is an endocrine growth factor mainly secreted by the liver in response to a ketogenic diet and alcohol consumption. FGF21 signaling requires co-receptor β-klotho ...(KLB) co-acting with FGF receptors, which has pleiotropic metabolic effects, including induced hepatic fatty acid oxidation and ketogenesis, in human and animal models of obesity. We examined the hepatocyte-specific enhancer/promoter of FGF21 expression plasmids in high-fat diet-fed mice for 12 weeks. Hydrodynamic injection for FGF21 delivery every 6 weeks sustained high circulating levels of FGF21, resulting in marked reductions in body weight, epididymal fat mass, insulin resistance, and liver steatosis. FGF21-induced lipolysis in the adipose tissue enabled the liver to be flooded with fat-derived FFAs. The hepatic expression of Glut2 and Bdh1 was upregulated, whereas that of gluconeogenesis-related genes, G6p and Pepck, and lipogenesis-related genes, Srebp-1 and Srebp-2, was significantly suppressed. FGF21 induced the phosphorylation of AMPK at Thr172 and Raptor at ser792 and suppressed that of mTOR at ser2448, which downregulated mTORC1 signaling and reduced IRS-1 phosphorylation at ser1101. Finally, in the skeletal muscle, FGF21 increased Glut4 and Mct2, a membrane protein that acts as a carrier for ketone bodies. Enzymes for ketone body catabolism (Scot) and citrate cycle (Cs, Idh3a), and a marker of regenerating muscle (myogenin) were also upregulated via increased KLB expression. Thus, FGF21-induced lipolysis was continuously induced by a high-fat diet and fat-derived FFAs might cause liver damage. Hepatic fatty acid oxidation and ketone body synthesis may act as hepatic FFAs' disposal mechanisms and contribute to improved liver steatosis. Liver-derived ketone bodies might be used for energy in the skeletal muscle. The potential FGF21-related crosstalk between the liver and extraliver organs is a promising strategy to prevent and treat metabolic syndrome-related nonalcoholic steatohepatitis.
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