Influence of Dietary Cholesterol on Mitochondrial Function in the Rat

Abstract

Rat-liver mitochondrial cholesterol ester levels were increased nine-fold and free cholesterol levels were doubled by feeding 10% lard and 2% cholesterol with Purina rabbit chow pellets to weanling male Sprague-Dawley rats for 5 weeks. This resulted in depression of State 3 (ADP-stimulated) glutamate respiration and reduced sensitivity to inhibition of phosphyorylation by tetrabutylammonium bromide and oligomycin. Brain, heart, lung, spleen, kidney and testis mitochondrial functions were not responsive to changes in dietary cholesterol nor were increases noted in free cholesterol content; mitochondrial cholesterol esters in these six tissues remained at extremely low levels regardless of treatment. Inclusion of 0.01% oleyl-p-decylbenzene sulfonate (a hypocholesterolemic agent) in the 10% lard and 2% cholesterol diet prevented elevation of rat-liver cholesterol esters and restored "normal" mitochondrial functions of respiratory control. This compound had no lowering effect on the raised level of liver mitochondrial free cholesterol nor on the reduced mitochondrial sensitivity to the phosphorylation inhibitors. We concluded that cholesterol esters were associated with depression of liver mitochondrial respiratory control and that free cholesterol was related to desensitization of mitochondria to the phosphorylation inhibitors.

Aerobic capacity mediates susceptibility for the transition from steatosis to steatohepatitis

“…Excess dietary cholesterol results in hepatomegaly and steatosis, reduced liver complete and total FAO, and decreased ADP‐coupled mitochondrial respiration in rats (Rogers et al . ; Fungwe et al . ), while chemical inhibition of endogenous cholesterol synthesis increased hepatic mitochondrial and peroxisomal FAO with protection from NASH development (Roglans et al .…”

“…The roles of both maladaptive liver cholesterol metabolism and hepatic mitochondrial function have been widely investigated in the development of NAFLD (Min et al 2012;Arguello et al 2015;Bashiri et al 2016). Excess dietary cholesterol results in hepatomegaly and steatosis, reduced liver complete and total FAO, and decreased ADP-coupled mitochondrial respiration in rats (Rogers et al 1980;Fungwe et al 1993), while chemical inhibition of endogenous cholesterol synthesis increased hepatic mitochondrial and peroxisomal FAO with protection from NASH development (Roglans et al 2002;Park et al 2016). In the current study, WD reduced FAO (complete and incomplete) and MRC in both strains, but the LCR rats started at a lower level and remained lower than HCR rats.…”

Genetic ablation ofCyp8b1preserves host metabolic function by repressing steatohepatitis and altering gut microbiota composition

“…One of the most striking observations of our study was the protection from metabolic impairments that was conferred by the genetic deletion of Cyp8b1 Ϫ/Ϫ . Indeed, excessive levels of free cholesterol accumulate in hepatocyte mitochondrial membranes leading to a reduced mitochondrial respiratory output in the livers of NASH patients (22,34).…”

“…Recently, direct measurements in NASH patients revealed a 40% reduction in hepatic mitochondrial respiration and a higher incidence of insulin resistance (19). Previous studies have shown that dietary cholesterol induces JNK1-mediated mitochondrial injury, leading to a suppression of State 3 respiration in steatohepatitis (10,22,34).…”

“…These effects are known to be driven by the activation of the liver X receptor (LXR)-sterol regulatory element binding protein-1c (SREBP1c) pathway in the liver (31). It is also known that dietary cholesterol suppresses mitochondrial State 3 respiration in steatohepatitis via JNK1 (10,22,34). Therefore, we challenged Cyp8b1 ϩ/ϩ and Cyp8b1 Ϫ/Ϫ mice with the 12-wk HCD regimen and measured various metabolic parameters.…”