Abstract
Hypertension is an important risk factor for nonalcoholic steatohepatitis. We have previously demonstrated that hypertensive rats fed a high fat and cholesterol (HFC) diet incurred a more severe hepatic inflammatory response and fibrosis. Here we investigated the role of hypertension in NASH by comparing HFC-induced hepatic fibrogenesis between spontaneously hypertensive rats (SHRs) and their normotensive Wistar Kyoto counterpart. Compared to the counterpart, the HFC diet led to stronger aggregation of CD68-positive macrophages in SHRs. HFC feeding also resulted in significantly higher upregulation of the fibrosis-related gene alpha-smooth muscle actin in SHR. The HFC diet induced higher overexpression of serum tissue inhibitor of metalloproteinase-1 (TIMP1) and greater suppression of matrix metalloproteinase-2 (MMP2):TIMP1, MMP8:TIMP1, and MMP9:TIMP1 ratios, as a proxy of the activities of these MMPs in SHR. Administration of the antihypertensive agent hydralazine to SHRs significantly ameliorated HFC-induced liver fibrosis; it suppressed the aggregation of CD68-positive macrophages and the upregulation of platelet-derived growth factor receptor beta, and collagen, type 1, alpha-1 chain. In conclusion, a hypertensive environment exacerbated the hepatic fibrogenetic effects of the HFC diet; while the effects were partially reversed by the antihypertensive agent hydralazine. Our data suggest that antihypertensive drugs hold promise for treating NASH exacerbated by hypertension.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases worldwide
We hypothesized that hypertension exacerbates hepatic fibrosis by aggravating high fat and cholesterol (HFC)-induced imbalance between extracellular matrix (ECM) synthesis and degradation, and the effect of hypertension on fibrogenesis can be reversed by antihypertensive therapy; to this end, we further investigated how antihypertensive therapy with hydralazine, a peripheral arterial vasodilator, ameliorated HFC-induced fibrogenesis in spontaneously hypertensive rats (SHRs)
We determined that hepatic fibrosis induced by the HFC diet was exacerbated in a hypertensive environment due, at least in part, to reduced MMP activity and the concomitantly reduced degradation of the ECM
Summary
Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases worldwide. Its aggressive form, nonalcoholic steatohepatitis (NASH), can progress to cirrhosis and end-stage liver disease and increase both morbidity and mortality [1]. Hydralazine reduced extracellular matrix synthesis and liver fibrosis. Regarded as a hepatic manifestation of metabolic syndrome, NAFLD is frequently associated with hypertension and insulin resistance [2,3]. A higher incidence of NAFLD and NASH in patients with hypertension has been reported relative to the normotensive population [4,5]. Ikuta et al showed that hypertension might enhance the progression of NASH in association with a reduction in the antioxidant capacity of the liver [6]. The relationship between hypertension and NAFLD is highly complex, and many aspects remain unclear
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