Synergistic interaction of dietary cholesterol and dietary fat in inducing experimental steatohepatitis

Abstract

The majority of patients with nonalcoholic fatty liver disease (NAFLD) have “simple steatosis,” which is defined by hepatic steatosis in the absence of substantial inflammation or fibrosis and is considered to be benign. However, 10%–30% of patients with NAFLD progress to fibrosing nonalcoholic steatohepatitis (NASH), which is characterized by varying degrees of hepatic inflammation and fibrosis, in addition to hepatic steatosis, and can lead to cirrhosis. The cause(s) of progression to fibrosing steatohepatitis are unclear. We aimed to test the relative contributions of dietary fat and dietary cholesterol and their interaction on the development of NASH. We assigned C57BL/6J mice to four diets for 30 weeks: control (4% fat and 0% cholesterol); high cholesterol (HC; 4% fat and 1% cholesterol); high fat (HF; 15% fat and 0% cholesterol); and high fat, high cholesterol (HFHC; 15% fat and 1% cholesterol). The HF and HC diets led to increased hepatic fat deposition with little inflammation and no fibrosis (i.e., simple hepatic steatosis). However, the HFHC diet led to significantly more profound hepatic steatosis, substantial inflammation, and perisinusoidal fibrosis (i.e., steatohepatitis), associated with adipose tissue inflammation and a reduction in plasma adiponectin levels. In addition, the HFHC diet led to other features of human NASH, including hypercholesterolemia and obesity. Hepatic and metabolic effects induced by dietary fat and cholesterol together were more than twice as great as the sum of the separate effects of each dietary component alone, demonstrating significant positive interaction. Conclusion Dietary fat and dietary cholesterol interact synergistically to induce the metabolic and hepatic features of NASH, whereas neither factor alone is sufficient to cause NASH in mice.

Hypercholesterolemic diet induces hepatic steatosis and alterations in mRNA expression of NADPH oxidase in rat livers

“…Recent reports suggest that dietary cholesterol is a critical factor in the development of experimental steatohepatitis in animal models (16). Human studies also support the hypothesis that dietary cholesterol plays a role in the development of steatohepatitis.…”

“…In an epidemiological study, it was reported that dietary cholesterol consumption was independently associated with the development of cirrhosis (17). In mice, the presence of triacylglycerol and cholesterol in the diet are needed for the development of both hepatic histological abnormalities of NASH and its associated metabolic abnormalities (16).…”

Dietary high-fat lard intake induces thyroid dysfunction and abnormal morphology in rats

“…Zucker diabetic fatty rats, a model of obesity secondary to genetic leptin unresponsiveness, rapidly accumulated triglycerides in the heart, which was accompanied by left ventricular remodeling and septal wall thickening [28] . Regarding the liver, many studies in mice [7] and rats [29] have documented high-fat diet induced fat accumulation in the liver and hepatic steatosis. These findings demonstrate that a high-fat diet may promote triglyceride accumulation in non-adipose tissues; the results of the present study convincingly show that a high-fat lard diet increased thyroid triglyceride content.…”

“…However, excess dietary fat intake promotes ectopic accumulation of triglycerides and free fatty acids in non-adipose depots, known as lipotoxicity, which contributes to chronic cellular dysfunction and injury [2][3][4] . In recent years, lipotoxicity has been well documented in the pathogenesis of many diabetes-related metabolic diseases [5][6][7][8][9] . In fact, in the early 1990s, dietary fat overabundance was reported to interfere with the endocrine system [10] .…”

The development of a clinical score for the prediction of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease using routine parameters

“…Therefore, the elevation of ApoB/ApoA1 ratio implies that non-HDL levels are increasing and/or HDL levels are decreasing. Elevated non-HDL levels can lead to the accumulation of lipids within hepatocytes; the resulting increase in free fatty acid levels causes lipotoxicity and lipid peroxidation, impairing hepatocytes and resulting in the development of NASH (20,21).…”