A High-Calorie Diet Aggravates Mitochondrial Dysfunction and Triggers Severe Liver Damage in Wilson Disease Rats

Abstract

Background & Aims In Wilson disease, ATP7B mutations impair copper excretion into bile. Hepatic copper accumulation may induce mild to moderate chronic liver damage or even acute liver failure. Etiologic factors for this heterogeneous phenotype remain enigmatic. Liver steatosis is a frequent finding in Wilson disease patients, suggesting that impaired copper homeostasis is linked with liver steatosis. Hepatic mitochondrial function is affected negatively both by copper overload and steatosis. Therefore, we addressed the question of whether a steatosis-promoting high-calorie diet aggravates liver damage in Wilson disease via amplified mitochondrial damage. Methods Control Atp7b +/- and Wilson disease Atp7b -/- rats were fed either a high-calorie diet (HCD) or a normal diet. Copper chelation using the high-affinity peptide methanobactin was used in HCD-fed Atp7b -/- rats to test for therapeutic reversal of mitochondrial copper damage. Results In comparison with a normal diet, HCD feeding of Atp7b -/- rats resulted in a markedly earlier onset of clinically apparent hepatic injury. Strongly increased mitochondrial copper accumulation was observed in HCD-fed Atp7b -/- rats, correlating with severe liver injury. Mitochondria presented with massive structural damage, increased H 2 O 2 emergence, and dysfunctional adenosine triphosphate production. Hepatocellular injury presumably was augmented as a result of oxidative stress. Reduction of mitochondrial copper by methanobactin significantly reduced mitochondrial impairment and ameliorated liver damage. Conclusions A high-calorie diet severely aggravates hepatic mitochondrial and hepatocellular damage in Wilson disease rats, causing an earlier onset of the disease and enhanced disease progression.

Fat and Sugar—A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease

“…Feeding a WD to the LPP rat led to an earlier onset of the disease at approximately 3 weeks and a significantly more severe course of the disease. Liver mitochondria of WD-fed LPP rats were severely affected, with separated inner and outer membranes, excessive matrix condensation and swollen cristae [226]. This study further underlines the important influence of dietary intake on liver mitochondrial morphology and function.…”

“…In a recent study, a WD was applied in the LPP rat model of Wilson's disease [226]. Wilson's disease is a genetic disorder of copper homeostasis that is frequently associated with liver steatosis and is, therefore, often misdiagnosed as NAFLD [227,228].…”

Mitochondrial stress protein HSP60 regulates ER stress-induced hepatic lipogenesis

“…HSP60, an important mitochondrial stress protein, has been shown to play key roles in the protein synthesis, folding, and delivery of misfolded proteins to proteolytic enzymes in the mitochondrial matrix (Tatsuta 2009, Haynes & Ron 2010, Hu & Liu 2011, Marino Gammazza et al 2018. Recent studies have showed that mitochondrial stress is associated with mitochondrial dysfunction and metabolic disorders such as hepatic steatosis, insulin resistance, and type 2 diabetes (Venojarvi et al 2008, Hu & Liu 2011, Comert et al 2019, Einer et al 2019. ER and mitochondria have partially overlapping functions, and there is strong crosstalk between the two organelles to regulate hepatic steatosis (Haynes & Ron 2010, Hu & Liu 2011, Ghemrawi et al 2018.…”

Extending the mode of action of triethylenetetramine (trientine): Autophagy besides copper chelation

“…5 Thus, insufficient autophagy may contribute to the initiation and progression of WD, in line with the observation that obesity, a state in which autophagy is inhibited due to the excess of nutrients, aggravates WD. 7 Of note, a minimal amount of copper is required for the initiation of the autophagic cascade, as copper binds to and stimulates the kinase activity of the pro-autophagic kinases, Unc-51 like autophagy activating kinases 1 and 2 (ULK1, ULK2). Complete depletion of copper hence blocks autophagy.…”