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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is a liver pathology diagnosed in subjects consuming little or no alcohol, not presenting secondary causes of hepatic steatosis [1] and in which at least 5% of hepatocytes are infiltrated with steatosis [2]
Male Wistar rats (Harlan Laboratories, Udine, Italy) weighing 200–220 g, 1-month-old, were divided into five groups, each including four animals: control rats (Ctrl) fed with a standard lab chow (24% protein, 65% carbohydrate, 11% fat), ad libitum water; rats maintained on a standard diet plus 10% (w/v) fructose dissolved in the drinking water (Fructose); high fat (HF) rats maintained on a 17% protein, 53% carbohydrate and 26% fat plus 4% cholesterol diet; rats fed with the HF diet plus 10% (w/v) fructose in the drinking water (HF-F); and rats maintained on the high-fat plus fructose (HF-F) diet fortified with 0.01% (w/w) DHEA (HF-F-D group)
We suggest that DHEA can delay the progression from NAFLD to nonalcoholic steatohepatitis (NASH) by buffering, through its antioxidant effects, the amplification at cell level of the oxidative stress, acting on those markers related to processes downstream of the mitochondrial oxidative stress, such as the inflammatory process and fibrosis
Summary
Nonalcoholic fatty liver disease (NAFLD) is a liver pathology diagnosed in subjects consuming little or no alcohol, not presenting secondary causes of hepatic steatosis [1] and in which at least 5% of hepatocytes are infiltrated with steatosis [2]. The initial “two-hit theory”, according to which accumulation of fatty acids in the liver (the characteristic steatosis) should constitute the first hit, followed by a second one, due to oxidative stress, activating the cascade of inflammatory cytokines that leads to the damage of liver parenchyma [9], has been substituted by the more recent “multiple parallel hits theory” [10] According to the latter, several “multiple parallel (and not sequential)” hits, including IR, oxidative stress, genetic and epigenetic factors, intestinal microbiota composition, and environmental elements, should cooperate to induce triglyceride accumulation in hepatocytes. In recent years, because of the marked relevance of nutrition on onset and progression of NAFLD, several different animal models, in which the applied diet leads to the disease, have been developed Among such obesogenic models, one based on a high-fat diet plus fructose (HF-F) has previously been analyzed by our group for its involvement of SREBP-1c in the generation of hepatic steatosis and for the induction of liver insulin resistance in rats [14]. DHEA is a compound of physiological origin with multitargeted antioxidant properties that was previously demonstrated
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