Cholesterol burden in the liver induces mitochondrial dynamic changes and resistance to apoptosis

Abstract

Non-alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of histopathological changes ranging from non-inflammatory intracellular fat deposition to non-alcoholic steatohepatitis (NASH), which may progress into hepatic fibrosis, cirrhosis, or hepatocellular carcinoma. Recent data suggest that impaired hepatic cholesterol homeostasis and its accumulation are relevant to the pathogenesis of NAFLD/NASH. Despite a vital physiological function of cholesterol, mitochondrial dysfunction is an important consequence of dietary-induced hypercholesterolemia and was, subsequently, linked to many pathophysiological conditions. The aim in the current study was to evaluate the morphological and molecular changes of cholesterol overload in mouse liver and particularly, in mitochondria, induced by a high-cholesterol (HC) diet for one month. Histopathological studies revealed microvesicular hepatic steatosis and significantly elevated levels of liver cholesterol and triglycerides leading to impaired liver synthesis. Further, high levels of oxidative stress could be determined in liver tissue as well as primary hepatocyte culture.Transcriptomic changes induced by the HC diet involved disruption in key pathways related to cell death and oxidative stress as well as upregulation of genes related to glutathione homeostasis. Impaired liver function could be associated with a decrease in mitochondrial membrane potential and ATP content and significant alterations in mitochondrial dynamics. We demonstrate that cholesterol overload in the liver leads to mitochondrial changes which may render damaged hepatocytes proliferative and resistant to cell death whereby perpetuating liver damage. K E Y W O R D S apoptosis, cholesterol, mitochondrial dynamics, oxidative stress J Cell Physiol. 2019;234:7213-7223. wileyonlinelibrary.com/journal/jcp Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Domínguez-Pérez M, Simoni-Nieves A, Rosales P, et al. Cholesterol burden in the liver induces mitochondrial dynamic changes and resistance to apoptosis.

Niemann–Pick type C disease: cellular pathology and pharmacotherapy

“…(Koh et al ; Klein et al ; Kennedy et al ) Most workers attribute this respiratory impairment not to loss of cyt c , or structurally aberrant mitochondria more generally, but to excess mitochondrial cholesterol poisoning the organelle. This hypothesis is superficially appealing and also consistent with mitochondrial dysfunction induced by cholesterol over‐feeding in hepatic (Domínguez‐Pérez et al ) and pancreatic (Asalla et al ) cells. Perhaps significantly, increased contacts between mitochondria and endosomes, and correspondingly decreased contacts between ER and endosomes, have recently been reported in NPC1‐deficient cells (Höglinger et al ).…”

Anti-cancer effect of doxorubicin is mediated by downregulation of HMG-Co A reductase via inhibition of EGFR/Src pathway

“…Although mitochondria are cholesterol-low organelles, several lines of studies have reported that cholesterol levels of mitochondria isolated from hepatic cancer cells are elevated and that this phenomenon is correlated with resistance to apoptotic cell death [37][38][39]. In addition, compared with chow diet-fed mice, hepatocytes from high-cholesterol-dietfed mice increase levels of not only pro-apoptotic Bax protein but also anti-apoptotic proteins, Mcl-1 and Bcl-xL as a compensatory anti-apoptosis response [39].…”

Cholesterol enrichment in liver mitochondria impairs oxidative phosphorylation and disrupts the assembly of respiratory supercomplexes

“…Mitochondrial cholesterol accumulation is a hallmark of chronic diseases, including cardiovascular disorders, cancer and Alzheimer's disease [[21], [22], [23], [24], [25], [26], [27], [28]]. In addition, previous studies have shown an association between increased mitochondrial cholesterol levels and liver injury in alcoholic and nonalcoholic liver disease [[29], [30], [31], [32], [33], [34]]. However, the specific role of mitochondrial cholesterol accumulation in mitochondrial respiration and organization of functional respiratory complexes has not been previously examined.…”