Saturated fat and cholesterol are critical to inducing murine metabolic syndrome with robust nonalcoholic steatohepatitis

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome (MetS). Up to a third of NAFLD subjects are at risk for developing nonalcoholic steatohepatitis (NASH). Many rodent models fail to replicate both MetS and NASH. The purpose of this study was to develop a reliable mouse model of NASH and MetS using a diet containing cholesterol, saturated fat and carbohydrate that is reflective of Western diets of North Americans. Experimental design: We used adult male C57BL/6 J 4- to 5-week-old mice and administered a solid diet containing 0.2% cholesterol, 45% of its calories from fat, with 30% of the fat in the form of partially hydrogenated vegetable oil. We also provided carbohydrate largely as high-fructose corn syrup equivalent in water. In a separate cohort, we gave the identical diet in the absence of cholesterol. Glucose and insulin tolerance testing was conducted throughout the feeding period. The feeding was conducted for 16 weeks, and the mice were sacrificed for histological analysis, markers of MetS, liver inflammation, circulating lipids, as well as liver staining for fibrosis and alpha smooth muscle actin (α-SMA). Results: We found that cholesterol significantly increased serum leptin, interleukin-6, liver weight and liver weight/body weight ratio, fibrosis and liver α-SMA. Conclusions: Mice administered a diet accurately reflecting patterns associated with humans afflicted with MetS can reliably replicate features of MetS, NASH and significant liver fibrosis. The model we describe significantly reduces the time by several months for development of stage 3 hepatic fibrosis.

Dietary cholesterol induces hepatic inflammation and blunts mitochondrial function in the liver of high-fat-fed mice

“…Regardless of these considerations, our results demonstrated an important role of cholesterol in converting simple hepatic steatosis to NASH while on an HF diet and with moderate hepatic steatosis. A recent study showed that addition of 0.2% cholesterol to an HF diet (45 kcal%, composed of high fat and trans-fat) induced robust NASH in mice when supplemented with sucrose in the drinking water [30]. Our results clearly showed that neither dietary cholesterol nor HF alone produced the NASH phenotype.…”

Updates on Dietary Models of Nonalcoholic Fatty Liver Disease: Current Studies and Insights

“…As previously stated, a Western diet is a diet high in saturated fat, trans-fat, and table sugar 19,20 . In humans, this type of diet has been shown to induce obesity, metabolic syndrome, NAFL and potentially NASH 19,20 .…”

“…The Western diet, which is a diet high in saturated fat, trans-fat, and table sugar, is thought to play a role in the development of metabolic syndrome and has been shown to increase the risk of developing it 19,20 . Given the association between metabolic syndrome and NAFLD in humans, researchers attempting to better understand NAFLD have developed various mouse model diets in order to mimic the Western diet.…”

Effects of glucomannan/spirulina-surimi on liver oxidation and inflammation in Zucker rats fed atherogenic diets

“…These data suggest that cholesterol feeding further increased the liver inflammation present in fa/fa rats, although there seems to have been a compensatory effect from activation of nitric oxide production. Mells et al [22] reported increased TNF-α on a high-fat, high-cholesterol fed metabolic syndrome murine model, suggesting a clear relationship between cholesterol feeding and liver inflammation.…”