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Fulltext Fructose-Drinking Water Induced Nonalcoholic Fatty Liver Disease and Ultrastructural Alteration of Hepatocyte Mitochondria in Male Wistar Rat

Mamikutty N, Thent ZC, Haji Suhaimi F

Biomed Res Int, 2015;2015:895961.
PMID: 26273656 DOI: 10.1155/2015/895961

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the complications of the metabolic syndrome. It encompasses a wide range of disease spectrum from simple steatosis to liver cirrhosis. Structural alteration of hepatic mitochondria might be involved in the pathogenesis of NAFLD.
AIMS: In the present study, we used a newly established model of fructose-induced metabolic syndrome in male Wistar rats in order to investigate the ultrastructural changes in hepatic mitochondria that occur with fructose consumption and their association with NAFLD pathogenesis.
METHODS: The concentration of fructose-drinking water (FDW) used in this study was 20%. Six male Wistar rats were supplemented with FDW 20% for eight weeks. Body composition and metabolic parameters were measured before and after 8 weeks of FDW 20%. Histomorphology of the liver was evaluated and ultrastructural changes of mitochondria were assessed with transmission electron micrograph.
RESULTS: After 8 weeks of fructose consumption, the animals developed several features of the metabolic syndrome. Moreover, fructose consumption led to the development of macrovesicular hepatic steatosis and mitochondrial ultrastructural changes, such as increase in mitochondrial size, disruption of the cristae, and reduction of matrix density.
CONCLUSION: We conclude that in male Wistar rat 8-week consumption of FDW 20% leads to NAFLD likely via mitochondrial structural alteration.

Matched MeSH terms: Mitochondria, Liver/drug effects*; Mitochondria, Liver/ultrastructure*
Influence of palm oil or its tocotrienol-rich fraction on the lipid peroxidation potential of rat liver mitochondria and microsomes

Nesaretnam K, Devasagayam TP, Singh BB, Basiron Y

Biochem. Mol. Biol. Int., 1993 May;30(1):159-67.
PMID: 8358328

The effect of palm oil, a widely used vegetable oil, rich in tocotrienols, on peroxidation potential of rat liver was examined. Long-term feeding of rats with palm oil as one of the dietary components significantly reduced the peroxidation potential of hepatic mitochondria and microsomes. As compared to hepatic mitochondria isolated from rats fed control or corn oil-rich diet, those from palm oil-fed group showed significantly less susceptibility to peroxidation induced by ascorbate and NADPH. However, in microsomes, only NADPH-induced lipid peroxidation was significantly reduced in rats fed palm oil rich-diet. Though the accumulation of thiobarbituric acid reactive substances during ascorbate-induced lipid peroxidation in mitochondria from rats fed corn oil-rich diet supplemented with tocotrienol-rich fraction (TRF) of palm oil was similar to that of control rats, the initial rate of peroxidation was much slower than those from control or corn oil fed diets. Our in vitro studies as well as analyses of co-factors related to peroxidation potential indicated that the observed decrease in palm oil-fed rats may be due to increased amount of antioxidants in terms of tocotrienol as well as decrease in the availability of substrates for peroxidation.

Matched MeSH terms: Mitochondria, Liver/drug effects*; Mitochondria, Liver/metabolism
Inhibition of mitochondrial functions by margosa oil: possible implications in the pathogenesis of Reye's syndrome

Koga Y, Yoshida I, Kimura A, Yoshino M, Yamashita F, Sinniah D

Pediatr Res, 1987 Aug;22(2):184-7.
PMID: 3658544

Margosa oil (MO), a fatty acid-rich extract of the seeds of the neem tree and a reported cause of Reye's syndrome, has been used in the induction of an experimental model of Reye's syndrome in rats. It has been reported that MO causes a decrease in in vivo mitochondrial enzyme activity similar to that seen in Reye's syndrome. We have attempted to uncover some of the biochemical mechanisms of MO's toxicity by examining its effect in vitro on isolated rat liver mitochondria. Male rat liver mitochondria were isolated by centrifugation; oxygen uptake, reduced forms of cytochrome b, c + c1, a + a3, and flavoprotein, intramitochondrial concentrations of acetyl coA, acid-soluble coA, acid-insoluble coA, and ATP content were measured after incubation with and without MO. Our results reveal that MO is a mitochondrial uncoupler. State 4 respiration was increased while the respiratory control ratio was decreased. The intramitochondrial content of ATP was also decreased. There were substantial changes in the reduction of the respiratory chain components after incubation of mitochondria with MO. This decelerative effect on mitochondrial electron transport was alleviated by the addition of coenzyme Q and/or carnitine. These effects of MO on mitochondrial respiration may be due to changes in fatty acid metabolism caused by MO as MO caused a shift in the proportion of acid-soluble or acid-insoluble coA esters. Supplementary therapy with L-carnitine and coenzyme Q may be useful in the management of MO-induced Reye's syndrome.

Matched MeSH terms: Mitochondria, Liver/drug effects*; Mitochondria, Liver/metabolism
Fulltext Mitochondrial hepatopathies: advances in genetics, therapeutic approaches, and outcomes

Lee WS, Sokol RJ

J Pediatr, 2013 Oct;163(4):942-8.
PMID: 23810725 DOI: 10.1016/j.jpeds.2013.05.036
Matched MeSH terms: Mitochondria, Liver/pathology
Mitochondrial targeting of bilirubin regulatory enzymes: An adaptive response to oxidative stress

Muhsain SN, Lang MA, Abu-Bakar A

Toxicol Appl Pharmacol, 2015 Jan 1;282(1):77-89.
PMID: 25478736 DOI: 10.1016/j.taap.2014.11.010

The intracellular level of bilirubin (BR), an endogenous antioxidant that is cytotoxic at high concentrations, is tightly controlled within the optimal therapeutic range. We have recently described a concerted intracellular BR regulation by two microsomal enzymes: heme oxygenase 1 (HMOX1), essential for BR production and cytochrome P450 2A5 (CYP2A5), a BR oxidase. Herein, we describe targeting of these enzymes to hepatic mitochondria during oxidative stress. The kinetics of microsomal and mitochondrial BR oxidation were compared. Treatment of DBA/2J mice with 200mgpyrazole/kg/day for 3days increased hepatic intracellular protein carbonyl content and induced nucleo-translocation of Nrf2. HMOX1 and CYP2A5 proteins and activities were elevated in microsomes and mitoplasts but not the UGT1A1, a catalyst of BR glucuronidation. A CYP2A5 antibody inhibited 75% of microsomal BR oxidation. The inhibition was absent in control mitoplasts but elevated to 50% after treatment. An adrenodoxin reductase antibody did not inhibit microsomal BR oxidation but inhibited 50% of mitochondrial BR oxidation. Ascorbic acid inhibited 5% and 22% of the reaction in control and treated microsomes, respectively. In control mitoplasts the inhibition was 100%, which was reduced to 50% after treatment. Bilirubin affinity to mitochondrial and microsomal CYP2A5 enzyme is equally high. Lastly, the treatment neither released cytochrome c into cytoplasm nor dissipated membrane potential, indicating the absence of mitochondrial membrane damage. Collectively, the observations suggest that BR regulatory enzymes are recruited to mitochondria during oxidative stress and BR oxidation by mitochondrial CYP2A5 is supported by mitochondrial mono-oxygenase system. The induced recruitment potentially confers membrane protection.

Matched MeSH terms: Mitochondria, Liver/drug effects; Mitochondria, Liver/enzymology*
Dentatin from Clausena excavata Induces Apoptosis in HepG2 Cells via Mitochondrial Mediated Signaling

Andas AR, Abdul AB, Rahman HS, Sukari MA, Abdelwahab SI, Samad NA, et al.

Asian Pac J Cancer Prev, 2015;16(10):4311-6.
PMID: 26028091

Hepatocellular carcinoma (HCC) is a primary liver cancer with high global incidence and mortality rates. Current candidate drugs to treat HCC remain lacking and those in use possess undesirable side effects. In this investigation, the antiproliferative effects of dentatin (DTN), a natural coumarin, were evaluated on HepG2 cells and DTN's probable preliminary molecular mechanisms in apoptosis induction were further investigated. DTN significantly (p<0.05) suppressed proliferation of HepG2 cells with an IC50 value of 12.0 μg/mL, without affecting human normal liver cells, WRL-68 (IC50>50 μg/mL) causing G0/G1 cell cycle arrest via apoptosis induction. Caspase colorimetric assays showed markedly increased levels of caspase-3 and caspase-9 activities throughout the treatment period. Western blotting of treated HepG2 cells revealed inhibition of NF-κB that triggers the mitochondrial-mediated apoptotic signaling pathway by up-regulating cytoplasmic cytochrome c and Bax, and down-regulating Bcl-2 and Bcl-xL. The current findings suggest DTN has the potential to be developed further as an anticancer compound targeting human HCC.

Matched MeSH terms: Mitochondria, Liver/drug effects; Mitochondria, Liver/metabolism