Bile Acid Metabolism is an Intermediary Factor between Non-Alcoholic Steatohepatitis and Ischemic Heart Disease in SHRSP5/Dmcr Rats

Abstract

The non-alcoholic steatohepatitis (NASH) increases the cardiovascular risk regardless of risk factors in metabolic syndrome. The stroke-prone (SP) spontaneously hypertensive rats (SHRSP5/Dmcr), fed a high-fat and-cholesterol (HFC) diet and administered Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) presented NASH and cardiovascular disease. However, the intermediary factors between NASH and cardiovascular risk are still unknown. We investigated whether bile acids (BAs) play an intermediary role between NASH and cardiovascular disease in SHRSP5/Dmcr rats. SHRSP5/Dmcr rats divided into 2 groups were fed an SP (non-NASH group, n=7) or HFC diet (NASH group, n=10) for 8 weeks. L-NAME was administered intraperitoneally in the final 2 weeks. In the NASH group, total BA levels were increased in both serum and liver; they aggravated the endothelial dysfunction in aorta, which is the first step to atherosclerosis, and activated the gene expression levels of cell adhesion molecules (vascular cell adhesion molecule-1, intercellular adhesion molecule-1) in coronary artery. In particular, the nuclear factor-kappa B (NFkB) was increased in the NASH group in the coronary endothelial cells activated by high BA levels. We demonstrated that liver BAs aggravated steatosis and fibrosis and serum BA accelerated arteriosclerosis and ischemic heart disease via the classical pathway of NFkB in the endothelial cells. BA metabolism disorder may be an intermediary factor between NASH and cardiovascular risk in SHRSP5/Dmcr rats.

Antioxidant action of xanthine oxidase inhibitor febuxostat protects the liver and blood vasculature in SHRSP5/Dmcr rats

“…Malondialdehyde (MDA), an oxidative stress marker in the liver, was measured by outsourcing to the Japan Institute for the Control of Aging (Nikken SEIL Co., Ltd., Shizuoka, Japan). The aorta was cut into 2 mm rings to evaluate the endothelial function, and the mesenteric artery was separated from the mesenteric adipose tissue for Oil Red O staining (Kumazaki et al, 2019;Watanabe et al, 2018).…”

“…Oil Red O staining of the mesenteric artery was performed as previously described (Kumazaki et al, 2019;Watanabe et al, 2018). The mesenteric artery was carefully isolated from the intestine and fixed in 10% formalin for 10 min.…”