The Mitochondrial Trigger in an Animal Model of Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the leading liver chronic disease featuring hepatic steatosis. Mitochondrial β-oxidation participates in the derangement of lipid metabolism at the basis of NAFLD, and mitochondrial oxidative stress contributes to the onset of the disease. We evaluated the presence and effects of mitochondrial oxidative stress in the liver from rats fed a high-fat plus fructose (HF-F) diet inducing NAFLD. Supplementation with dehydroepiandrosterone (DHEA), a multitarget antioxidant, was tested for efficacy in delaying NAFLD. A marked mitochondrial oxidative stress was originated by all diets, as demonstrated by the decrease in Superoxide Dismutase 2 (SOD2) and Peroxiredoxin III (PrxIII) amounts. All diets induced a decrease in mitochondrial DNA content and an increase in its oxidative damage. The diets negatively affected mitochondrial biogenesis as shown by decreased peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α), mitochondrial transcription factor A (TFAM), and the COX-IV subunit from the cytochrome c oxidase complex. The reduced amounts of Beclin-1 and lipidated LC3 II form of the microtubule-associated protein 1 light chain 3 (LC3) unveiled the diet-related autophagy’s decrease. The DHEA supplementation did not prevent the diet-induced changes. These results demonstrate the relevance of mitochondrial oxidative stress and the sequential dysfunction of the organelles in an obesogenic diet animal model of NAFLD.

Altered Mitochondrial Quality Control in Rats with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) Induced by High-Fat Feeding

“…In the relaxed state, mtDNA is accessible for replication by the minimum mitochondrial replisome, which is formed by the hexameric DNA helicase TWINKLE, the tetrameric mtSSB, and the mtDNA polymerase POLγ [ 59 ]. Our results demonstrated that in the liver of MAFLD rats the significantly reduced expression levels of TFAM correspond to a decreased amount of the mtDNA copy number and an impaired expression of the key enzymes of the mitochondrial replisome machinery, further supporting the role of TFAM in the control of mtDNA levels in response to altered metabolic states [ 60 , 61 ].…”

Comparison of copper concentration between non-alcoholic fatty liver disease patients and normal individuals: A meta-analysis

“…Further, it was unclear what the severity of the disease was in the included studies (as an invasive test, people who were biopsied might have increased pre-test probability of more severe disease). According to Mendoza et al, advanced brosis may increase hepatic copper concentrations, which was part of the reason why that study excluded patients with high liver tissue copper (19); (6) we were unable to address the competing etiologies of copper de ciency and excess; (7) in the liver tissue studies, there are few controls for comparison, in part because of the invasive biopsy procedure required.…”

“…Serum copper is mainly transported by binding to ceruloplasmin which regulates the distribution and release of copper and later played its biological roles ( 6 ). Copper is an indispensable trace element that serves as a structural and enzymatic cofactor for various antioxidant proteins, including cytochrome c oxidase (COX), superoxide dismutase (SOD), and ceruloplasmin ( 7 ). Excessive or deficient copper can lead to mitochondrial dysfunction or dyslipidemia ( 8 ).…”

Prognostic value and immune infiltration analyses of cuproptosis-related genes in hepatocellular carcinoma

“…In addition, copper deficiency is closely associated with mitochondrial dysfunction and oxidative stress [10]. Decreased liver cellular copper content causes abnormal mitochondrial enlargement, thereby leading to mitochondrial dysfunction [11]. Copper deficiency in the body also leads to abnormal antioxidant function, thus resulting in an aberrant oxidative stress response.…”