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Gupte MiP2010

From Bioblast
Gupte AA, Liu JZ, Ren Y, Minze LJ, Wiles JR, Collins AR, Lyon CJ, Hsueh WA (2010) Age- and diet-related mitochondrial dysfunction in a novel mouse model of metabolic syndrome is rescued by treatment with a PPARγ agonist

Link: Abstracts Session 2

Gupte AA, Liu JZ, Ren Y, Minze LJ, Wiles JR, Collins AR, Lyon CJ, Hsueh WA (2010)

Event: MiP2010

Nonalcoholic Steatohepatitis (NASH), which is closely associated with metabolic syndrome (MS), is the most common cause of chronic liver disease in the Western world, but has no approved treatment. Mitochondrial dysfunction and oxidative stress associated with MS have been proposed as major pathophysiological disturbances that contribute to NASH [1]. We thus investigated whether a novel MS mouse model of age- and diet-associated NASH had liver mitochondrial dysfunction and whether treatment with rosiglitazone (RSG, an insulin-sensitizing Peroxisome Proliferator-Activated Receptor γ (PPARγ) agonist) could alter this phenotype.


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Organism: Mouse  Tissue;cell: Liver 



HRR: Oxygraph-2k 


Full text

Nonalcoholic Steatohepatitis (NASH), which is closely associated with metabolic syndrome (MS), is the most common cause of chronic liver disease in the Western world, but has no approved treatment. Mitochondrial dysfunction and oxidative stress associated with MS have been proposed as major pathophysiological disturbances that contribute to NASH [1]. We thus investigated whether a novel MS mouse model of age- and diet-associated NASH had liver mitochondrial dysfunction and whether treatment with rosiglitazone (RSG, an insulin-sensitizing Peroxisome Proliferator-Activated Receptor γ (PPARγ) agonist) could alter this phenotype.

Young (3-month-old) and middle-aged (12-month-old) male LDLR-/- mice were fed 3 months of chow, high-fat diet (HFD) or HFD+RSG (1.2 g RSG/kg of HFD), and their livers were then analyzed for changes in gene expression, oxidative stress, histology and mitochondrial function. Respiration of isolated liver mitochondria in response to 5 mM palmitoyl carnitine, glutamate-malate or succinate with and without 150 μM ADP was determined using a Clark-type electrode. Gene expression was analyzed with quantitative RT-PCR.

Middle-aged LDLR-/- mice fed 3 months of HFD (MS mice) developed MS (obesity, elevated fasting glucose and triglycerides, and decreased HDL) [2], and revealed a classic NASH phenotype of liver steatosis, inflammation and fibrosis. RSG treatment dramatically reduced NASH in these MS mice. Liver oxidative stress, measured by F2α-isoprostane levels, was dramatically increased in MS mice, but prevented by RSG treatment. Palmitoyl-carnitine dependent State 3 respiration and respiration control ratios (RCR=State 3/State 4), indicative of fatty acid oxidation (FAO), were increased in HFD-fed young but not middle-aged mice. RSG treatment normalized RCRs of MS mice to those of HFD-fed young mice (young HFD 5.33±0.26 vs. middle-aged HFD 4.65±0.21 and HFD+RSG 5.68±0.31, P<0.05). ATP:O ratios were significantly reduced with age for all 3 substrates. However, RSG trended to increase ATP:O ratios and oligomycin-sensitive respiration rates in MS mice. RSG also reversed HFD-mediated decreases in liver FAO genes (CPT1, ACADm, HADHa), and attenuated HFD-induced decreases in antioxidant genes (Nrf2, CAT, SOD2, GPX-1 and -4) in middle-aged mice. HFD increased the expression of mitochondrial gene Cox5a in young mice, but not in MS mice; but RSG induced it.

Our data indicate that aging exacerbates HFD-induced alterations in liver histology, metabolism, and oxidative stress, leading to NASH. Young mice fed HFD exhibit an adaptive response to increase FAO. However, aging dampened this adaptive response. Moreover, decreased ATP:O ratios in the middle-aged animals suggest reduced mitochondrial efficiency. Thus, our data suggests that age-related mitochondrial dysfunction may lead to impaired FAO and thereby, at least in part, cause accumulation of lipid in the livers of MS mice.

RSG treatment significantly increased FAO as seen by both respiration with palmitoyl carnitine and by gene expression of FAO enzymes, and was mirrored by the dramatic reduction of steatosis with RSG. To our knowledge this is the first report showing RSG can enhance FAO. RSG’s role in improving antioxidant capacity appears to directly influence mitochondrial function since mitochondria are the main source of reactive oxygen species in cells [1]. These observations have implications for development of new strategies to prevent and treat NASH. However, further studies are warranted to understand the mechanisms by which RSG protects mitochondrial function and reduces oxidative stress.

1. Serviddio G, Sastre J, Bellanti F, Viña J, Vendemiale G, Altomare E (2008) Mitochondrial involvement in non-alcoholic steatohepatitis. Mol. Aspects Med. 29: 22-35.

2. Collins AR, Lyon CJ, Xia X, Liu JZ, Tangirala RK, Yin F, Boyadjian R, Bikineyeva A, Praticò D, Harrison DG, Hsueh WA (2009) Age-accelerated atherosclerosis correlates with failure to upregulate antioxidant genes. Circ. Res. 104:e42-54