Increased Glycine-conjugated and Unconjugated Bile Acid Levels Associated with Aggravation of Nonalcoholic Steatohepatitis and Cardiovascular Disease in SHRSP5/Dmcr Rat.

The SHRSP5/Dmcr is a useful animal model for the development of nonalcoholic steatohepatitis (NASH) pathology when fed a high-fat, high-cholesterol diet, and further drug interventions can lead to concomitant cardiovascular disease. While SHRSP5/Dmcr rats have been used for basic research related to NASH, details of their bile acid metabolism in this condition are unknown. In this study, we aimed to clarify the changes in the serum bile acid (BA) fractions associated with NASH and found that glycine-conjugated and unconjugated bile acid increased with worsening NASH and cardiovascular disease while taurine-conjugated BA relatively decreased.

Bile acids aggravate nonalcoholic steatohepatitis and cardiovascular disease in SHRSP5/Dmcr rat model.

BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) is linked to an increased risk of cardiovascular disease, regardless of the risk factors in metabolic syndrome. However, the intermediary factors between NASH and cardiovascular disease are still unknown. A previous study revealed that serum and hepatic bile acid (BA) levels are increased in some NASH patients. We aimed to examine whether NASH and cardiovascular disease were aggravated by BA using an animal model. METHOD AND RESULTS: From 10 to 18 weeks of age, SHRSP5/Dmcr rats divided into 3 groups were fed 3 types of high-fat and high-cholesterol (HFC) diets which were changed in the cholic acid (CA) concentration (0%, 2%, or 4%). The nitro oxide synthase inhibition (L-NAME) was administered intraperitoneally from 16 to 18 weeks of age. The 4% CA groups showed the worst LV dysfunction and myocardial fibrosis, and demonstrated severe hepatic fibrosis and lipid depositions. In addition, a large amount of lipid accumulation was observed in the aortas of the 4% CA group, and NFκB and VCAM-1 gene expression levels were increased. These findings were not seen in the 0% CA group. CONCLUSION: In the SHRSP5/Dmcr rat model, NASH and cardiovascular disease were aggravated with increasing BAs concentrations in an HFC diet.

Non-alcoholic steatohepatitis aggravates nitric oxide synthase inhibition-induced arteriosclerosis in SHRSP5/Dmcr rat model.

Non-alcoholic steatohepatitis (NASH) is linked to increased cardiovascular risk, independent of the broad spectrum of metabolic syndrome risk factors. Stroke-prone (SP) spontaneously hypertensive rats (SHRSP5/Dmcr) fed a high-fat and high-cholesterol (HFC) diet developed hepatic lesions similar to those in human NASH pathology. These rats simultaneously developed lipid deposits in the mesenteric arteries, cardiac fibrosis, endothelial dysfunction and left ventricle (LV) diastolic dysfunction. However, the intermediary factors between NASH and cardiovascular disease are still unknown. We investigated whether NASH aggravates nitric oxide (NO) synthase inhibition-induced arteriosclerosis in SHRSP5/Dmcr rats. Wistar Kyoto and SHRSP5/Dmcr rats were divided into 4 groups of 5 and fed the stroke-prone (SP) or HFC diets for 8 weeks. To induce NO synthase inhibition, Nω -nitro-L-arginine methyl ester hydrochloride (L-NAME) mixed with drinking water was administered in the final 2 weeks. The NASH+L-NAME group demonstrated the following characteristics related to arteriosclerosis and myocardial ischaemia: (a) LV systolic dysfunction with asynergy, (b) replacement fibrosis caused by the shedding of cardiomyocytes and (c) arterial lipid deposition and coronary occlusion secondary to endothelial dysfunction. These characteristics were not observed in the NASH or non-NASH+L-NAME groups. The SHRSP5/Dmcr rat model demonstrates that NASH significantly aggravates cardiovascular risk.

Basic characteristics between mechanomyogram and muscle force during twitch and tetanic contractions in rat skeletal muscles.

The mechanomyogram (MMG) is a signal measured by various vibration sensors for slight vibrations induced by muscle contraction, and it reflects the muscle force during electrically induced-contraction or until 60%-70% maximum voluntary contraction, so the MMG is considered an alternative and novel measurement tool for muscle strength. We simultaneously measured the MMG and muscle force in the gastrocnemius (GC), vastus intermedius (VI), and soleus (SOL) muscles of rats. The muscle force was measured by attaching a hook to the tendon using a load cell, and the MMG was measured using a charged-coupled device-type displacement sensor at the middle of the target muscle. The MMG-twitch waveform was very similar to that of the muscle force; however, the half relaxation time and relaxation time (10%), which are relaxation parameters, were prolonged compared to those of the muscle force. The MMG amplitude correlated with the muscle force. Since stimulation frequencies that are necessary to evoke tetanic progression have a significant correlation with the twitch parameter, there is a close relationship between twitch and tetanus in the MMG signal. Therefore, we suggest that the MMG, which is electrically induced and detected by a laser displacement sensor, may be an alternative tool for measuring muscle strength.

Suppression of nitric oxide synthase aggravates non-alcoholic steatohepatitis and atherosclerosis in SHRSP5/Dmcr rat via acceleration of abnormal lipid metabolism.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a progressive subtype of non-alcoholic fatty liver disease (NAFLD) that is closely related to cardiovascular disease (CVD). Nitric oxide (NO) plays a critical role in the control of various biological processes. Dysfunction of the NO signaling pathway is associated with various diseases such as atherosclerosis, vascular inflammatory disease, and diabetes. Recently, it has been reported that NO is related to lipid and cholesterol metabolism. Chronic NO synthase (NOS) inhibition accelerates NAFLD by increasing hepatic lipid deposition. However, the detailed relationship between NO and abnormal lipid and cholesterol metabolism in NAFLD/NASH has not been completely explained. We aimed to determine the effects of NOS inhibition by N omega-nitro-L-arginine methyl ester hydrochloride (L-NAME), a NOS inhibitor, on NASH and CVD via lipid and cholesterol metabolism. METHODS: Stroke-prone spontaneously hypertensive rats were fed a high-fat and high-cholesterol diet for 8 weeks and administered L-NAME for the last 2 weeks. Following blood and tissue sampling, biochemical analysis, histopathological staining, quantitative RT-PCR analysis, and western blotting were performed. RESULTS: L-NAME markedly increased hepatic triglyceride (TG) and cholesterol levels by promoting TG synthesis and cholesterol absorption from the diet. L-NAME increased the mRNA levels of inflammatory markers and fibrotic areas in the liver. Cholesterol secretion from the liver was promoted in rats administered L-NAME, which increased serum cholesterol. L-NAME significantly increased the level of oxidative stress marker and lipid deposition in the arteries. CONCLUSIONS: NOS inhibition simultaneously aggravates NASH and atherosclerosis via hepatic lipid and cholesterol metabolism.

A High-Fat and High-Cholesterol Diet Induces Cardiac Fibrosis, Vascular Endothelial, and Left Ventricular Diastolic Dysfunction in SHRSP5/Dmcr Rats.

AIM: Non-alcoholic steatohepatitis (NASH) increases cardiovascular risk regardless of risk factors in metabolic syndrome. However, the intermediary factors between NASH and vascular disease are still unknown because a suitable animal model has never been established. The stroke-prone (SP) spontaneously hypertensive rat, SHRSP5/Dmcr, simultaneously develops hypertension, acute arterial lipid deposits in mesenteric arteries, and NASH when feed with a high-fat and high-cholesterol (HFC) diet. We investigated whether SHRSP5/Dmcr affected with NASH aggravates the cardiac or vascular dysfunction. METHOD: Wister Kyoto and SHRSP5/Dmcr rats were divided into 4 groups of 5 rats each, and fed with a SP or HFC diet. After 8 weeks of HFC or SP diet feeding, glucose and insulin resistance, echocardiography, blood biochemistry, histopathological staining, and endothelial function in aorta were evaluated. RESULTS: We demonstrate that SHRSP5/Dmcr rats fed with a HFC diet presented with cardiac and vascular dysfunction caused by cardiac fibrosis, endothelial dysfunction, and left ventricular diastolic dysfunction, in association with NASH and hypertension. These cardiac and vascular dysfunctions were aggravated and not associated with the presence of hypertension, glucose metabolism disorder, and/or obesity. CONCLUSIONS: SHRSP5/Dmcr rats may be a suitable animal model for elucidating the organ interaction between NASH and cardiac or vascular dysfunction.