Development of novel rat model for high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis progression in SHRSP5/Dmcr

Abstract

Objectives Patients with nonalcoholic fatty liver disease are increasing worldwide, and preventive measures are an urgent need and primary concern today. Aim This study aimed to develop and clarify the usefulness of the SHRSP5/Dmcr rat, derived from a stroke-prone spontaneously hypertensive rat, as a novel animal model for time-course analysis of steatohepatitis and the severe fibrosis progression often observed in the disease. Methods Ten-week-old male SHRSP5/Dmcr rats were divided into six groups: half were fed a high-fat and highcholesterol-containing diet (HFC diet), and the others the control, stroke-prone (SP) diet for 2, 8, and 14 weeks.

Simultaneous changes in high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis and those underlying molecular mechanisms in novel SHRSP5/Dmcr rat

“…10) and conducted at Kinjo Gakuin University in accordance with its Animal Experiment Guidelines [8]. We obtained 30 male rat offspring at the age of 10 weeks that were used throughout our experiment; mating and housing has been described elsewhere [8].…”

“…They were provided with stroke-prone control chow (SP-diet) (Funabashi Farm, Chiba, Japan) [9] and water ad libitum. The nutrient components (weight %) of the SP-diet and the HFC-diet have been described earlier [8]. At 10 weeks of age, 30 male rats were randomized to six groups, of which three groups were fed SP-diet (control) and the remaining groups were fed HFC-diet for 2, 8, and 16 weeks, respectively.…”

“…A small liver section was fixed in 4% buffered paraformaldehyde. The remaining liver tissue and plasma were stored at -80°C until use [8].…”

“…This rat is registered at the National BioResource Project for the Rat in Japan [7] and represents the fifth substrain of the original SHRSP rat descended from the normotensive Wistar-Kyoto rat in Japan [8]. During an investigation of the effects of a high-fat and high-cholesterol-containing (HFC) diet on arteriosclerosis rats, carried out within the framework of a nutritional study, we incidentally found that the fibrotic liver of the SHRSP5/Dm rat showed extensive enlargement and a whitish color, with extensive lipid accumulation [8]. The HFC-diet-induced steatohepatitis and liver fibrosis in the SHRSP5/Dmcr rat reflected pathological features closely resembling the steatohepatitis and liver fibrosis progression in patients despite the absence of apparent hyperglycemia, insulin resistance, and obesity [8].…”

“…During an investigation of the effects of a high-fat and high-cholesterol-containing (HFC) diet on arteriosclerosis rats, carried out within the framework of a nutritional study, we incidentally found that the fibrotic liver of the SHRSP5/Dm rat showed extensive enlargement and a whitish color, with extensive lipid accumulation [8]. The HFC-diet-induced steatohepatitis and liver fibrosis in the SHRSP5/Dmcr rat reflected pathological features closely resembling the steatohepatitis and liver fibrosis progression in patients despite the absence of apparent hyperglycemia, insulin resistance, and obesity [8]. Based on these pathological findings, we expected to find perturbed lipid metabolism and increased inflammatory and pro-fibrogenic reactions when these rats were fed the HFC-diet.…”