Liver Cholesterol Overload Aggravates Obstructive Cholestasis by Inducing Oxidative Stress and Premature Death in Mice

Abstract

Nonalcoholic steatohepatitis is one of the leading causes of liver disease. Dietary factors determine the clinical presentation of steatohepatitis and can influence the progression of related diseases. Cholesterol has emerged as a critical player in the disease and hence consumption of cholesterol-enriched diets can lead to a progressive form of the disease. The aim was to investigate the impact of liver cholesterol overload on the progression of the obstructive cholestasis in mice subjected to bile duct ligation surgery. Mice were fed with a high cholesterol diet for two days and then were subjected to surgery procedure; histological, biochemical, and molecular analyses were conducted to address the effect of cholesterol in liver damage. Mice under the diet were more susceptible to damage. Results show that cholesterol fed mice exhibited increased apoptosis and oxidative stress as well as reduction in cell proliferation. Mortality following surgery was higher in HC fed mice. Liver cholesterol impairs the repair of liver during obstructive cholestasis and aggravates the disease with early fatal consequences; these effects were strongly associated with oxidative stress.

Effects of fermented ginseng root and ginseng berry on obesity and lipid metabolism in mice fed a high-fat diet

“…Long-term exposure to an HFD can cause nonalcoholic fatty liver disease, a condition wherein large droplets of fat deposited in hepatocytes via the process of steatosis. Some studies have suggested that the kind of lipid rather than the amount of fat determines the susceptibility to the second hit of the two-hit theory for the pathogenesis of nonalcoholic fatty liver disease [18] . Excessive cholesterol accumulation disrupts membrane fluidity, promotes cellular dysfunction, and thereby results in the progression fatty liver [19] .…”

Cholesterol overload in the liver aggravates oxidative stress-mediated DNA damage and accelerates hepatocarcinogenesis

“…We and others have been proved that the consumption of a high cholesterol diet induces a cholesterol overload in the liver rising a complex response in hepatocytes characterized by mitochondria dysfunction and oxidative stress [ 12 - 14 ], but, interestingly, hepatocytes with cholesterol overload seems to be resistant to cell death under unstimulated conditions. Nonetheless, they are sensitized to a second aggression, particularly those directed to mitochondria by a mechanism related to mitochondrial-glutathione depletion [ 14 ].…”

“…Animals were euthanized in parallel exclusively for in situ ROS determination [ 12 ]. Fresh tissue was rapidly sectioned, frozen in liquid nitrogen, and embedded in optimum cutting temperature reagent (OCT, Sakura Finetec, Torrance, CA).…”

“…Caspase 3 activity was quantified using the caspase 3 synthetic fluorogenic tetrapeptide substrate Ac-DEVD-AMC (BD Pharmingen) as previously we reported [ 12 ] using fresh liver tissue, values were normalized regarding Chow sample and reported as fold change.…”

La exposición a cadmio exacerba la hiperlipidemia en hepatocitos con sobrecarga de colesterol

“…Además, se ha propuesto que pacientes con sobrecarga de colesterol en hígado presentan más riesgo de desarrollar complicaciones clínicas asociadas con colestasis (Nuno-Lambarri et al,2016).…”