Complementary role of peripheral and central autonomic nervous system on insulin-like growth factor-1 activation to prevent fatty liver disease.

BACKGROUND: Insulin-like growth factor-1 (IGF-1) is involved in the pathology of non-alcoholic fatty liver disease (NAFLD) and ameliorates fatty infiltration in the liver. It is activated by growth hormone (GH); however, the role of GH-IGF-1 axis in NAFLD developmental phase has not been well identified. Therefore, in this study, we focused on the effect of IGF-1 in NAFLD pathology and GH excretion activation from the pituitary gland by peripheral autonomic neural pathways relaying liver-brain-gut pathway and by central neuropeptides. METHODS: GH and IGF-1 levels were assessed in wild-type and melanocortin-4 receptor knockout mice upon the development of diet-induced NAFLD. The contribution of the peripheral autonomic nervous system connecting the liver-brain-gut axis was assessed by its blockade using capsaicin and that of the central nervous system was assessed by the expression of hypothalamic brain-derived neurotrophic factor (BDNF) and corticotropin-releasing factor (CRH), which activates GH release from the pituitary gland. RESULTS: In the NAFLD mouse models, the levels of GH and IGF-1 increased (p < .05). Further, hepatic fatty infiltration was suppressed even under peripheral autonomic nervous system blockade (p < .001), which inhibited gastric ghrelin expression. In mice with peripheral autonomic nervous blockade, hypothalamic BDNF and CRH were inhibited (p < .05), resulting in GH and IGF-1 excretion, whereas other neuropeptides of somatostatin and cortistatin showed no changes. These complementary effects were canceled in melanocortin-4 receptor knockout mice, which diminished BDNF and CRH release control. CONCLUSIONS: Our study demonstrates that the release of IGF-1 by the nervous system is a key factor in maintaining the pathological homeostasis of NAFLD, suggesting its therapeutic potential.

Effects of a selective PPARα modulator, sodium-glucose cotransporter 2 inhibitor, and statin on the myocardial morphology of medaka nonalcoholic fatty liver disease model.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic dysregulation and is linked with various cardiovascular complications, which often lead to poor prognostic outcomes. To develop a standard therapy for NAFLD and to urgently address its complications, the current study aimed to investigate the mechanisms of NAFLD-related heart disease and the therapeutic effects of drugs targeting various metabolic pathways. METHODS: To explore the mechanism of NAFLD-related heart disease, a medaka model of high-fat diet-induced NAFLD was utilized. The gross structural, histological, and inflammatory changes in the myocardium were evaluated in a time-dependent manner. In addition, the therapeutic effects of medicines used for NAFLD treatment including, selective peroxisome proliferator-activated receptor α modulator (SPPARMα, pemafibrate), sodium-glucose cotransporter 2 (SGLT2) inhibitor (tofogliflozin), and statin (pitavastatin), and their combinations on heart pathology were evaluated. To determine the mechanisms underlying the therapeutic effects, the expression of genes related to liver inflammation was assessed via whole transcriptome sequencing analysis. RESULTS: The fish with NAFLD-related heart injury presented with cardiomyocyte hypertrophy, which led to cardiac hypertrophy. This morphological change was caused by the infiltration of inflammatory cells, including macrophages and CD4- and CD8-positive lymphocytes, in the cardiac wall and the expression of transforming growth factor beta 1 in the cardiomyocytes. Further, the livers of the fish had upregulated expressions of senescence-associated secretory phenotype-related genes. Treatment with pemafibrate, tofogliflozin, and pitavastatin reduced these changes and, consequently, cardiomyopathy. CONCLUSION: Our results demonstrated that NAFLD-related heart disease was attributed to the senescence-associated secretory phenotype-induced inflammatory activity in the cardiac wall, which resulted in myocardial hypertrophy. Moreover, the effects of SPPARMα, SGLT2 inhibitor, and statin on NAFLD-related heart disease were evident in the medaka NAFLD model.

Involvement of the liver-gut peripheral neural axis in nonalcoholic fatty liver disease pathologies via hepatic HTR2A.

Serotonin (5-HT) is one of the key bioamines of nonalcoholic fatty liver disease (NAFLD). Its mechanism of action in autonomic neural signal pathways remains unexplained; hence, we evaluated the involvement of 5-HT and related signaling pathways via autonomic nerves in NAFLD. Diet-induced NAFLD animal models were developed using wild-type and melanocortin 4 receptor (MC4R) knockout (MC4RKO) mice, and the effects of the autonomic neural axis on NAFLD physiology, 5-HT and its receptors (HTRs), and lipid metabolism-related genes were assessed by applying hepatic nerve blockade. Hepatic neural blockade retarded the progression of NAFLD by reducing 5-HT in the small intestine, hepatic HTR2A and hepatic lipogenic gene expression, and treatment with an HTR2A antagonist reproduced these effects. The effects were milder in MC4RKO mice, and brain 5-HT and HTR2C expression did not correlate with peripheral neural blockade. Our study demonstrates that the autonomic liver-gut neural axis is involved in the etiology of diet-induced NAFLD and that 5-HT and HTR2A are key factors, implying that the modulation of the axis and use of HTR2A antagonists are potentially novel therapeutic strategies for NAFLD treatment. This article has an associated First Person interview with the first author of the paper.

Modulation of serotonin in the gut-liver neural axis ameliorates the fatty and fibrotic changes in non-alcoholic fatty liver.

The etiology of non-alcoholic fatty liver disease (NAFLD) consists of various factors, including neural signal pathways. However, the molecular mechanisms of the autonomic neural signals influencing NAFLD progression have not been elucidated. Therefore, we examined the involvement of the gut-liver neural axis in NAFLD development and tested the therapeutic effect of modulation of this axis in this study. To test the contribution of the gut-liver neural axis, we examined NAFLD progression with respect to body weight, hepatic steatosis, fibrosis, intestinal tight junction, microbiota and short-chain fatty acids in NAFLD models of choline-deficient defined L-amino-acid and high-fat diet-fed mice with or without blockades of autonomic nerves from the liver. Blockade of the neural signal from the liver to the gut in these NAFLD mice models ameliorated the progression of liver weight, hepatic steatosis and fibrosis by modulating serotonin expression in the small intestine. It was related to the severity of the liver pathology, the tight junction protein expression, microbiota diversity and short-chain fatty acids. These effects were reproduced by administrating serotonin antagonist, which ameliorated the NAFLD progression in the NAFLD mice models. Our study demonstrated that the gut-liver neural axis is involved in the etiologies of NAFLD progression and that serotonin expression through this signaling network is the key factor of this axis. Therefore, modulation of the gut-liver neural axis and serotonin antagonist ameliorates fatty and fibrotic changes in non-alcoholic fatty liver, and can be a potential therapeutic target of NAFLD.This article has an associated First Person interview with the first author of the paper.

Synchronous Double Bile Duct Cancers with Distinct Genetic Features.

A 69-year-old man was referred to our hospital because of appetite loss. Imaging showed a nodular tumor in the perihilar bile duct and a second flat lesion in the distal bile duct. Right hepatopancreaticoduodenectomy was performed, and the histopathological findings demonstrated that the perihilar and distal lesions were moderately and poorly differentiated adenocarcinoma, respectively, and anatomically separated. Furthermore, the resected specimens showed no pancreaticobiliary maljunction. Histological and TP53 gene analyses in a rare case of synchronous double bile duct cancers suggest that there are various genetic pathways through which bile duct cancer develops, highlighting the complexity of its pathogenesis.

Rational arrangement of measuring shear wave speed in the liver.

BACKGROUND: Shear wave speed has been widely applied to quantify a degree of liver fibrosis. However, there is no standardized procedure, which makes it difficult to utilize the speed universally. AIM: To provide procedural standardization of shear wave speed measurement. METHODS: Point shear wave elastography (pSWE) was measured in 781 patients, and two-dimensional shear wave elastography (2dSWE) was measured on the same day in 18 cases. Regions-of-interest were placed at 12 sites, and the median and robust coefficient-of-variation (CVR) were calculated. A residual sum-of-square (Σdi 2) was computed for bootstrap values of 1000 iterations in 18 cases with each assumption of 1 to 12 measurements. The proportion of the Σdi 2 (%Σdi 2) was calculated as the ratio of Σdi 2 to pSWE after converting it based on the correlation between pSWE and 2dSWE. RESULTS: The CVR showed a significantly broader distribution in the left lobe (P < 0.0001), and the smallest CVR in the right anterior segment that covered 95% cases was 40.4%. pSWE was significantly higher in the left lobe than in the right lobe (1.63 ± 0.78 m/s vs 1.61 ± 0.78 m/s, P = 0.0004), and the difference between the lobes became further discrete when the subjects were limited to the cases with a CVR less than 40.4% in any segment (1.76 ± 0.80 m/s vs 1.70 ± 0.82 m/s, P < 0.0001). The highest values of the CVR in every 0.1 m/s interval were plotted in convex upward along pSWE and peaked at 1.93 m/s. pSWE and 2dSWE were significantly correlated (P < 0.0001, r = 0.95). In 216000 resamples from 18 cases, the %Σdi 2 of 12 sites was 8.0% and gradually increased as the acquisition sites decreased to reach a significant difference with a %Σdi 2 of 7 sites (P = 0.027). CONCLUSION: These data suggest that shear wave speed should be measured at 8 or more sites of spreading in both lobes.

A cut-off value of shear wave speed to distinguish nonalcoholic steatohepatitis candidates.

To distinguish and characterize nonalcoholic steatohepatitis (NASH) candidates from among medical checkup visitor diagnosed with nonalcoholic fatty liver diseases (mcNAFLDs).A cut-off value has not been established to differentiate NASH at the earliest stage in NAFLD.Shear wave speed (SWS) was measured in the livers of 480 mcNAFLDs. NASH candidates were screened out by adopting a statistically defined cut-off value of SWS and were characterized in terms of food preference.SWS ranged between 1.11 and 2.18 m/s and fit a Gaussian distribution (r = 0.98) with an average and SD of 1.324 and 0.0847 m/s, respectively, in 320/160 males/females 64.4 (interquartile range 57.3-69.4) years old. The average plus SD (1.41 m/s) screened out 82 (17.1%) NASH candidates, who were significantly older (66.8 vs. 64.1 years old, P = 0.001) and had higher fibrosis 4 index values (1.58 vs. 1.33, P < 0.0001) than the remaining mcNAFLDs. The number of patients with a BMI greater than 25 kg/m was 118 (29.6%) mcNAFLDs and 34 (41.5%) NASH candidates, with a significantly higher frequency in NASH candidates (P = 0.05). Obese patients preferentially ate fatty acids in general, while NASH candidates preferred to consume several long-chain unsaturated fatty acids irrespective of their BMI.These results suggest that NASH candidates who have a longer disease duration and pathological progression can be distinguished from mcNAFLDs by a statistically defined cut-off value of SWS. The defined value indicates that there are different food habitats associated with obesity and NAFLD progression.