Obesity and steatosis promotes mitochondrial remodeling that enhances respiratory capacity in the liver of ob/ob mice

Garcia, Jerome; Decker, Carl W.; Sanchez, Silvestre J.; Ouk, Jeffrey M.; Siu, Krysta M.; Han, Derick

doi:10.1002/1873-3468.13005

Cited by 13 publications

(10 citation statements)

References 48 publications

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“…Several studies have reported that mice with insulin resistance and NAFLD display increased hepatic mitochondrial content and excessive oxidative metabolism [38,39]. As this may be an important contributor to the exaggerated rates of EGP in NAFLD, we investigated the relationship between insulin resistance and hepatic mitochondrial remodeling.…”

Section: Hepatic Mitochondrial Remodeling In Insulin Resistancementioning

confidence: 99%

Insulin Resistance is Mechanistically Linked to Hepatic Mitochondrial Remodeling in Nonalcoholic Fatty Liver Disease

et al. 2020

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Section: Hepatic Mitochondrial Remodeling In Insulin Resistancementioning

confidence: 99%

Insulin Resistance is Mechanistically Linked to Hepatic Mitochondrial Remodeling in Nonalcoholic Fatty Liver Disease

et al. 2020

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“…Since insulin resistance and NAFLD are characterized by excessive oxidative liver metabolism and mitochondrial remodeling (9, 22), we compared markers of mitochondrial content in livers from wild-type (WT) mice with those from OB-CON and OB-PIO mice. Citrate synthase activity (Figure 1A) and complex IV protein expression (Figure 1B) were increased 30 and 70%, respectively, in OB-CON compared to WT, whilst VDAC1 protein was unchanged (Figure 1B).…”

Section: Resultsmentioning

confidence: 99%

Hepatic Mitochondrial Remodeling is Mechanistically Linked to Insulin Resistance in Nonalcoholic Fatty Liver Disease

Shannon

Ragavan

Palavicini

et al. 2020

Preprint

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Alterations in hepatic mitochondrial function are a feature of type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) and may precipitate the development of fibrosis and steatohepatitis. Using multi-dimensional mass spectrometry-based shotgun lipidomics we show that livers of insulin-resistant obese mice display extensive remodeling of the mitochondrial lipid cardiolipin, which may increase susceptibility to oxidative stress. This is exacerbated by excessive mitochondrial fatty acid delivery, evidenced by long-chain acylcarnitine accumulation, and is accompanied by increased TCA cycle activity and hyperactivation of pyruvate dehydrogenase. Moreover, insulin-sensitization with pioglitazone rescued cardiolipin remodeling and reduced mitochondrial pyruvate metabolism by simultaneously suppressing pyruvate carboxylase flux and inhibiting PDH activation through PDK4 induction / PDP2 suppression.These pioglitazone-derived benefits were entirely dissociated from changes in hepatic triglyceride or diacylglyceride levels. Our findings identify targetable mitochondrial features of T2D and NAFLD and highlight the benefit of insulin sensitization in managing the clinical burden of obesity-associated disease. a combination of 2 H / 13 C NMR metabolic flux analyses, high-resolution lipidomics and molecular approaches. RESULTS Pioglitazone rescues hepatic mitochondrial lipid remodeling in obese mice:To investigate whether the disease-modifying actions of pioglitazone are linked to effects on hepatic mitochondrial function, we fed obese (ob/ob) 12-week-old mice a diet supplemented with pioglitazone (300 mg/kg diet) for four weeks. Consistent with human studies (10), pioglitazone-treated obese mice (OB-PIO) displayed rapid improvements in fasting blood glucose, oral glucose tolerance ( Figure S1A) and peripheral insulin sensitivity compared to untreated obese mice (OB-CON) ( Table 1). These metabolic improvements occurred despite significantly greater weight gain in OB-PIO mice, which was due to increases in both lean and fat mass compared to OB-CON mice (Table 1) and is in accordance with the weight gain observed in human patients treated with pioglitazone (21). Moreover, pioglitazone did not improve hepatic lipid accumulation and, on the contrary, total liver triglycerides and diacylglycerides were both ~30% greater in OB-PIO mice compared to OB-CON (Table 1). Together, these data illustrate that intrahepatic lipid accumulation per se can be dissociated from the beneficial effects of pioglitazone upon insulin sensitivity.Since insulin resistance and NAFLD are characterized by excessive oxidative liver metabolism and mitochondrial remodeling (9, 22), we compared markers of mitochondrial content in livers from wildtype (WT) mice with those from OB-CON and OB-PIO mice. Citrate synthase activity ( Figure 1A) and complex IV protein expression ( Figure 1B) were increased 30 and 70%, respectively, in OB-CON compared to WT, whilst VDAC1 protein was unchanged ( Figure 1B). Remarkably, all markers of mitochondrial content we...

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“…Western blot was conducted as per our previous work [ 18 ]. Aliquots of cytoplasmic or mitochondrial extracts were fractionated by electrophoresis on 8–12% SDS polyacrylamide gels (BioRad, Hercules, CA).…”

Section: Methodsmentioning

confidence: 99%

“…Respiration was measured in freshly isolated mitochondria according to our prior work [ 20 ] by monitoring oxygen consumption with a Clark‐type electrode (Hanstech, UK) in respiration buffer containing 230 mm mannitol, 70 mm sucrose, 30 mm Tris–HCl, 5 mm KH 2 PO 4 , 1 mm EDTA, pH 7.4 [ 9 ]. Control and treated Jurkat suspensions with digitonin applied were added to 1 mL of respiration buffer and oxygen consumption monitored in the presence of mitochondrial Complex I substrates (glutamate/malate 7.5 mM) with or without ADP (250 μM).…”

Section: Methodsmentioning

confidence: 99%

Mitofusin-2 mediates doxorubicin sensitivity and acute resistance in Jurkat leukemia cells

Decker

Garcia

Gatchalian

et al. 2020

Biochemistry and Biophysics Reports

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Mitochondria oscillate along a morphological continuum from fragmented individual units to hyperfused tubular networks. Their position at the junction of catabolic and anabolic metabolism couples this morphological plasticity, called mitochondrial dynamics, to larger cellular metabolic programs, which in turn implicate mitochondria in a number of disease states. In many cancers, fragmented mitochondria engage the cell with the biosynthetic capacity of aerobic glycolysis in service of proliferation and progression. Chemo-resistant cancers, however, favor remodeling dynamics that yield fused mitochondrial assemblies utilizing oxidative phosphorylation (OXPHOS) through the electron transport chain (ETC). In this study, expression of Mitofusin-2 (MFN-2), a GTPase protein mediator of mitochondrial fusion, was found to closely correlate to Jurkat leukemia cell survival post doxorubicin (DxR) assault. Moreover, this was accompanied by dramatically increased expression of OXPHOS respiratory complexes and ATP Synthase, as well as a commensurate escalation of state III respiration and respiratory control ratio (RCR). Importantly, CRISPR knockout of MFN-2 resulted in a considerable decrease of doxorubicin (DxR) median lethal dose compared to a treated wildtype control, suggesting an important role of mitochondrial fusion in chemotherapy sensitivity and acute resistance.

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Obesity and steatosis promotes mitochondrial remodeling that enhances respiratory capacity in the liver of ob/ob mice

Cited by 13 publications

References 48 publications

Insulin Resistance is Mechanistically Linked to Hepatic Mitochondrial Remodeling in Nonalcoholic Fatty Liver Disease

Insulin Resistance is Mechanistically Linked to Hepatic Mitochondrial Remodeling in Nonalcoholic Fatty Liver Disease

Hepatic Mitochondrial Remodeling is Mechanistically Linked to Insulin Resistance in Nonalcoholic Fatty Liver Disease

Mitofusin-2 mediates doxorubicin sensitivity and acute resistance in Jurkat leukemia cells

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