Synergistic interaction of fatty acids and oxysterols impairs mitochondrial function and limits liver adaptation during nafld progression

Abstract

The complete mechanism accounting for the progression from simple steatosis to steatohepatitis in nonalcoholic fatty liver disease (NAFLD) has not been elucidated. Lipotoxicity refers to cellular injury caused by hepatic free fatty acids (FFAs) and cholesterol accumulation. Excess cholesterol autoxidizes to oxysterols during oxidative stress conditions. We hypothesize that interaction of FAs and cholesterol derivatives may primarily impair mitochondrial function and affect biogenesis adaptation during NAFLD progression. We demonstrated that the accumulation of specific non-enzymatic oxysterols in the liver of animals fed high-fat+high-cholesterol diet induces mitochondrial damage and depletion of proteins of the respiratory chain complexes. When tested in vitro, 5α-cholestane-3β,5,6β-triol (triol) combined to FFAs was able to reduce respiration in isolated liver mitochondria, induced apoptosis in primary hepatocytes, and down-regulated transcription factors involved in mitochondrial biogenesis. Finally, a lower protein content in the mitochondrial respiratory chain complexes was observed in human non-alcoholic steatohepatitis. In conclusion, hepatic accumulation of FFAs and non-enzymatic oxysterols synergistically facilitates development and progression of NAFLD by impairing mitochondrial function, energy balance and biogenesis adaptation to chronic injury.

Hypoxic Signaling and Cholesterol Lipotoxicity in Fatty Liver Disease Progression

“…A synergistic interaction between FFA and oxysterols was suggested to impair mitochondrial function in NASH. Accumulation of specific nonenzymatic oxysterols and FFA induces mitochondrial damage and depletion of proteins of the respiratory chain complexes and mitochondrial biogenesis both in vivo and in vitro [ 101 ]. Targeted lipidomic analysis of a rat liver with steatohepatitis identified oxysterol triols (e.g., cholestane-3 β ,5 α ,6 β -triol) that were associated with mitochondrial dysfunction and hepatocyte toxicity [ 102 ].…”

Redox Control of the Immune Response in the Hepatic Progenitor Cell Niche

“…Mitochondria (through the respiratory chain), the endoplasmic reticulum (through cytochrome P450) and Kupffer cells (through NADPH oxidase) are the main sources of ROS (Louvet and Mathurin, 2015). An impairment in redox balance is also described in non-alcoholic fatty liver disease (NAFLD), where free fatty acid excess causes overproduction of reactive species mostly by mitochondria and cytochrome P450 (Serviddio et al, 2011a(Serviddio et al, ,b, 2013bBellanti et al, 2017Bellanti et al, , 2018, which lead to a pro-oxidative environment triggering the release of pro-inflammatory cytokines, which in turn activate hepatic stellate cells to produce connective These reactive species can be classified as free radicals, characterized by one or more unpaired electrons in their outer shell, and non-radical derivatives.…”

Localisation of oxysterols at the sub-cellular level and in biological fluids

“…Fatty acid and cholesterol accumulation in hepatocytes undergoes lipid peroxidation to form oxysterols that causes impairment of mitochondrial function, biogenesis and depletion of respiratory chain complexes in non-alcoholic fatty liver disease (NAFLD) [81,82]. A related study showed that when hepatocytes were exposed to the combination of fatty acids (palmitic and oleic) and oxysterol cholestane-3β,-5α,-6β-triol, they showed mitochondrial dysfunction [83,84]. There is evidence for alterations in the oxysterol profiles and the synergistic interaction of free fatty acids and oxysterols, impairing mitochondrial biogenesis, which underpins the progression of liver disease [82,83].…”

“…A related study showed that when hepatocytes were exposed to the combination of fatty acids (palmitic and oleic) and oxysterol cholestane-3β,-5α,-6β-triol, they showed mitochondrial dysfunction [83,84]. There is evidence for alterations in the oxysterol profiles and the synergistic interaction of free fatty acids and oxysterols, impairing mitochondrial biogenesis, which underpins the progression of liver disease [82,83]. 7β-OHC, 7KC…”

“…and triol concentrations were elevated in NAFLD and were associated with increased H2O2 production, uncoupling and impaired ATP homeostasis in mitochondria and induced mitochondriadependent apoptosis [83,[85][86][87]. In human and rat hepatocellular tumour cells, there were increased levels of cholesterol in mitochondrial membranes that altered membrane dynamics, contributing to mitochondrial dysfunction [45].…”