**Author details**

**Figure 1.** Possible mechanism underlying pathogenesis of HFC diet-induced fibrotic steatohepatitis in hypertensive SHRSP5/Dmcr rats [25, 35, 47]. In response to cholesterol accumulation in the liver triggered by HFC feeding, de novo cholesterol synthesis and its uptake were suppressed, indicated by a reduction in HMGCR, as well as LDLR and LPR1. The HFC diet induced dysregulated BA synthesis (upregulated CYP7A1 and CYP7B1, as well as downregulated CYP8B1 and CYP27A1) and export (downregulated BSEP and MRP2, as well as upregulated MRP3), and led to BA accumulation in hepatocytes. In addition, the HFC diet suppressed BA detoxification by decreasing the expression of nuclear receptors (PXR and CAR), and further downregulating SULT2A1 and UGT1A1, BA detoxification enzymes. Furthermore, cytotoxic BA accumulation in hepatocytes-induced oxidative stress, which activated inflammatory signaling (TNF-α, TGF-β/NF-κB, MAPK) and resulted in hepatitis. Hepatic inflammation-induced upregulation of fibrosis-related genes (α-SMA, PDGF-β, Col1a1) and led to hepatic fibrosis. Additionally, hypertension enhanced the deterioration of HFC-induced fibrotic steatohepatitis by upregulating CYP7A1, further leading to BA accumulation in hepatocytes and increased oxidative stress. On the other hand, hypertension induced the suppression of anti-oxidative signaling (Nrf-2/Keap1) following HFC feeding. Therefore, elevated oxidative stress and suppressed anti-oxidative capacity triggered a more severe inflammatory response in the hypertensive rats fed an HFC diet, as indicated by increased activation of inflammatory signaling (TNF-α, TGF-β/NF-κB, MAPK). BA, bile acid; HMGCR, 3-hydroxy 3-methyl-glutaryl-coenzyme A reductase; LDLR, low density lipoprotein receptor; LRP1, LDLR-related protein 1; CYP7A1, cholesterol 7α-hydroxylase; CYP8B1, sterol 12α-hydroxylase; CYP27A1, sterol 27-hydroxylase; CYP7B1, oxysterol 7α-hydroxylase; BSEP, bile salt export pump; MRP2, multidrug resistance-associated protein 2; MRP3, multidrug resistance-associated protein 3; FXR, farnesoid X receptor; PXR, pregnane X receptor; CAR, constitutive adrostane receptor; SULT2A1, sulfotransferase 2A1; UGT1A1, UDP-glucoronosyltransferase 1A1; TNF-α, tumor necrosis factor-α; TGF-β, transforming growth factor; NF-κB, nuclear factor kappa B; MAPK, mitogen-activated protein kinase; α-SMA, α-smooth muscle actin; PDGF-B, plateletderived growth factor subunit B; Col1a1, alpha 1 type 1 collagen; Nrf-2, nuclear factor erythroid 2-related factor 2;

Keap1, Kelch-like ECH-associated protein 1.

118 Cholesterol - Good, Bad and the Heart

Yuan Yuan1 , Hisao Naito2 and Tamie Nakajima<sup>1</sup> \*

