Fat Diet-induced Fatty Liver Disease Research Articles

Kadukkai maathirai (Siddha herbal formulation) reverses liver pathology associated with metabolic dysfunction in high fat diet-induced fatty liver disease – a preclinical study

The study explores the hepatoprotective effect of Kadukkai maathirai (KM) in high fat diet (HFD) induced nonalcoholic fatty liver disease (NAFLD) in rats. Total 54 Sprague Dawley rats were used in the study, 9 groups: Group I – IV kept as normal and test drug control and group V - NAFLD disease model- received HFD for 40 weeks. Group VI – IX received HFD for 40 weeks and then test drugs: Group VI – VIII received KM in three different doses for 45 days. Metformin (standard) was administered to Group IX for 45 days. On day 46, the blood and liver tissue were collected for analysis. KM at 36, 144mg/kg and metformin showed a significant decrease in ALP level, all three doses of KM and metformin showed a significant reduction in direct bilirubin levels. A significant improvement in HDL was observed in all doses of KM and metformin-treated groups. Oral glucose tolerance test (OGTT) findings in KM treated test groups showed significantly reduced plasma glucose levels. The KM treated groups and metformin-treated groups showed a reduction in body weight at 47th week, and significantly reduced relative liver weight when compared with the HFD group. Histopathological evaluation of KM treated groups showed normal architecture of central vein and hepatic cords. Portal triads were also generally normal in their location and pattern. No indication of fatty liver. This study confirms the ability of phytoconstituents present in KM in reversing the metabolic dysfunction and liver pathology seen in NAFLD. Further studies are required to evaluate KM as a therapeutic agent.

Proteomics approach to investigate dynamic protein profile involved in high fat diet-induced fatty liver disease in rats.

Nonalcoholic fatty liver disease (NAFLD) is a disorder of the liver found worldwide. The molecular mechanisms underlying NAFLD initiation and progression, however, remain poorly understood. In this study, fluorescence difference gel electrophoresis (DIGE) combined with mass spectrometry was performed to profile the intracellular processes in the rat liver at the proteome level when rats were fed a high-fat diet for 8 weeks. Dynamic changes of 27 protein spots were observed. Among them, upregulation of 14 spots and downregulation of 13 spots were observed during the eight weeks of the high fat diet-induction period. These spots were analyzed by matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF), and ultimately 24 proteins were identified with more than 95% confidence. Gene ontology (GO) annotation indicated that these proteins were implicated in the metabolism of carbohydrates, lipids, and amino acids. Four proteins were validated by western blot. Further functional studies on these dynamically changing proteins may lead to a better understanding of the mechanisms of high fat diet-induced fatty liver disease.

Facilitation of Ca2+ -induced opening of the mitochondrial permeability transition pore either by nicotinamide nucleotide transhydrogenase deficiency or statins treatment.

Mitochondrial redox imbalance and high Ca2+ uptake induce the opening of the permeability transition pore (PTP) that leads to disruption of energy-linked mitochondrial functions and triggers cell death in many disease states. In this review, we discuss the major results from our studies investigating the consequences of NAD(P)-transhydrogenase (NNT) deficiency, and of statins treatment for mitochondrial functions and susceptibility to Ca2+ -induced PTP. We highlight the aggravation of high fat diet-induced fatty liver disease in the context of NNT deficiency and the role of antioxidants in the prevention of statins toxicity to mitochondria.

Redox imbalance due to the loss of mitochondrial NAD(P)-transhydrogenase markedly aggravates high fat diet-induced fatty liver disease in mice

The mechanisms by which a high fat diet (HFD) promotes non-alcoholic fatty liver disease (NAFLD) appear to involve liver mitochondrial dysfunctions and redox imbalance. We hypothesized that a HFD would increase mitochondrial reliance on NAD(P)-transhydrogenase (NNT) as the source of NADPH for antioxidant systems that counteract NAFLD development. Therefore, we studied HFD-induced liver mitochondrial dysfunctions and NAFLD in C57Unib.B6 congenic mice with (Nnt+/+) or without (Nnt-/-) NNT activity; the spontaneously mutated allele (Nnt-/-) was inherited from the C57BL/6J mouse substrain. After 20 weeks on a HFD, Nnt-/- mice exhibited a higher prevalence of steatohepatitis and content of liver triglycerides compared to Nnt+/+ mice on an identical diet. Under a HFD, the aggravated NAFLD phenotype in the Nnt-/- mice was accompanied by an increased H2O2 release rate from mitochondria, decreased aconitase activity (a redox-sensitive mitochondrial enzyme) and higher susceptibility to Ca2+-induced mitochondrial permeability transition. In addition, HFD led to the phosphorylation (inhibition) of pyruvate dehydrogenase (PDH) and markedly reduced the ability of liver mitochondria to remove peroxide in Nnt-/- mice. Bypass or pharmacological reactivation of PDH by dichloroacetate restored the peroxide removal capability of mitochondria from Nnt-/- mice on a HFD. Noteworthy, compared to mice that were chow-fed, the HFD did not impair peroxide removal nor elicit redox imbalance in mitochondria from Nnt+/+ mice. Therefore, HFD interacted with Nnt mutation to generate PDH inhibition and further suppression of peroxide removal. We conclude that NNT plays a critical role in counteracting mitochondrial redox imbalance, PDH inhibition and advancement of NAFLD in mice fed a HFD. The present study provide seminal experimental evidence that redox imbalance in liver mitochondria potentiates the progression from simple steatosis to steatohepatitis following a HFD.

Melatonin attenuates high fat diet-induced fatty liver disease in rats

To investigate melatonin's preventive action in oxidative stress in a rat model with high fat diet-induced non-alcoholic fatty liver disease (NAFLD). NAFLD was induced by high fat diet (HFD) in adult, male, Wistar rats, weighing 180-230 g. After acclimatization for one week, they were randomly assigned to 6 experimental groups that comprised animals on regular diet plus 5 or 10 mg/kg melatonin, for 4 or 8 wk; animals on HFD, with or without 5 or 10 mg/kg melatonin, for 4 or 8 wk; and animals on HFD for 8 or 12 wk, with melatonin 10 mg/kg for the last 4 wk. Liver damage was assessed biochemically by the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and histologically. Lipid peroxidation and oxidative stress were assessed by malondialdehyde and glutathione levels in liver tissue. Lipidemic indices and portal vein pressure were also measured. Compared to rats not receiving melatonin, rats on 5 or 10 mg/kg of melatonin had lower mean liver weight (-5.0 g and -4.9 g) (P < 0.001) and lower liver weight to body weight ratio (-1.0%) (P < 0.001), for the two doses, respectively. All rats fed HFD without melatonin developed severe, grade III, steatosis. Rats on HFD with concurrent use of melatonin showed significantly less steatosis, with grade III steatosis observed in 1 of 29 (3.4%) rats on 10 mg/kg melatonin and in 3 of 27 (11.1%) rats on 5 mg/kg melatonin. Melatonin was ineffective in reversing established steatosis. Melatonin also had no effect on any of the common lipidemic serum markers, the levels of which did not differ significantly among the rats on HFD, irrespective of the use or not of melatonin. Liver cell necrosis was significantly less in rats on HFD receiving melatonin than in those not on melatonin, with the AST levels declining by a mean of 170 U/L (P = 0.01) and 224 U/L (P = 0.001), and the ALT levels declining by a mean of 62.9 U/L (P = 0.01) and 93.4 U/L (P < 0.001), for the 5 and 10 mg/kg melatonin dose, respectively. Melatonin mitigated liver damage due to peroxidation and oxidative stress in liver tissue as indicated by a significant decline in MDA production by 12.7 (P < 0.001) and 12.2 (P < 0.001) μmol/L /mg protein /mg tissue, and a significant increase in glutathione by 20.1 (P = 0.004) and 29.2 (P < 0.001) μmol/L /mg protein /mg tissue, for the 5 and 10 mg/kg melatonin dose, respectively. Melatonin can attenuate oxidative stress, lessen liver damage, and improve liver histology in rats with high fat diet-induced NAFLD, when given concurrently with the diet.

Treatment of Non-alcoholic Fatty Liver Disease with the Carotenoid Zeaxanthin in a Quail Model

Purpose: Non-alcoholic fatty liver disease (NAFLD) is associated with insulin resistance and the development of Type II diabetes mellitus. Inflammation and oxidative stress have been implicated in the development of NAFLD and metabolic syndrome. We have previously shown that the carotenoid zeaxanthin showed a strong anti-oxidant and protective effect in a model of methionine-choline deficiency-induced steatohepatitis. [1] In this study we assessed the effects of zeaxanthin treatment on high fat diet-induced fatty liver disease and insulin resistance. Methods: Japanese quails (an established animal model for zeaxanthin) were reared on a carotenoid-deficient diet and then fed additional corn oil (18cc/ gr of feed, corresponding to a 33% increase in dietary fat consumption) for 4 weeks. Four experimental groups were analyzed in this study: quails not subjected to corn oil treatment (carotenoid-deficient diet control= CTRL, n=10), quails fed with corn oil (high fat diet group=HF, n=10), quails fed with HF diet and treated with 12.5mg/kg zeaxanthin administered orally every other day (HF+12.5, n=10) and quails fed with HF diet and treated with 25mg/kg zeaxanthin administered orally every other day (HF+25, n=10). At the end of treatment the animals were sacrificed and the livers and plasma were collected for histologic analysis and metabolic screening, respectively. Results: We found that only the HF group displayed steatosis (mild). The HF group also had circulating levels of triglycerides and insulin both significantly increased (approximately 3-fold, p<0.01) above CTRL. Treatment with zeaxanthin was able to significantly reduce insulin levels in a dose dependent manner (p<0.01) for HF+12.5 and HF+25 compared to HF. Treatment with HF+25 was able to significantly reduce triglyceride levels (p<0.01) compared to HF (see Table).Table: Table. Metabolic outcomes by treatment groupConclusion: The results of this study suggest that treatment with the carotenoid zeaxanthin may be beneficial in preventing the development of insulin resistance and hypertriglyceridemia associated with NAFLD and metabolic syndrome.