Pioglitazone improves hepatic mitochondrial function in a mouse model of nonalcoholic steatohepatitis

Kalavalapalli, Srilaxmi; Bril, Fernando; Koelmel, Jeremy P.; Abdo, Kaitlyn I; Guingab, Joy; Andrews, Paige; Li, Wenyi; Jose, Dhanya; Yost, Richard A.; Frye, Reginald F.; Garrett, Timothy J.; Cusi, Kenneth; Sunny, Nishanth E.

doi:10.1152/ajpendo.00023.2018

Cited by 55 publications

(54 citation statements)

References 42 publications

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“…As an insulin sensitizer, pioglitazone is widely used for treating insulin resistance. We choose pioglitazone as a positive control drug mainly based on previous study and other reports [ 12 , 13 , 14 ]. Paeoniflorin and pioglitazone were suspended in saline and given by oral gavage at 4 mL/kg for eight weeks.…”

Section: Methodsmentioning

confidence: 99%

Paeoniflorin Ameliorates Fructose-Induced Insulin Resistance and Hepatic Steatosis by Activating LKB1/AMPK and AKT Pathways

Qiao

Wang

et al. 2018

Nutrients

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The present study aimed to evaluate the effects of paeoniflorin on insulin resistance and hepatic steatosis induced by fructose. Male Sprague-Dawley rats were fed 20% fructose drink for eight weeks. The insulin sensitivity, serum lipid profiles, and hepatic lipids contents were measured. The results showed that paeoniflorin significantly decreased serum insulin and glucagon levels, improved insulin sensitivity and serum lipids profiles, and alleviated hepatic steatosis in fructose-fed rats. Moreover, paeoniflorin enhanced the phosphorylation level of AMP-activated protein kinase (AMPK) and protein kinase B (PKB/AKT) and inhibited the phosphorylation of acetyl coenzyme A carboxylase (ACC)1 in liver. Paeoniflorin also increased the hepatic carnitine palmitoyltransferase (CPT)-1 mRNA and protein expression and decreased the mRNA expression of sterol regulatory element-binding protein (SREBP)1c, stearyl coenzyme A decarboxylase (SCD)-1 and fatty acid synthetase (FAS). Furthermore, we found that paeoniflorin significantly increased the heptatic protein expression of tumor suppressor serine/threonine kinase (LKB)1 but not Ca2+/CaM-dependent protein kinase kinase (CaMKK)β. These results suggest that the protective effects of paeoniflorin might be involved in the activation of LKB1/AMPK and insulin signaling, which resulted in the inhibition of lipogenesis, as well as the activation of β-oxidation and glycogenesis, thus ameliorated the insulin resistance and hepatic steatosis. The present study may provide evidence for the beneficial effects of paeoniflorin in the treatment of insulin resistance and non-alcoholic fatty liver.

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Section: Methodsmentioning

confidence: 99%

Paeoniflorin Ameliorates Fructose-Induced Insulin Resistance and Hepatic Steatosis by Activating LKB1/AMPK and AKT Pathways

Qiao

Wang

et al. 2018

Nutrients

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“…Therefore, most guidelines do not recommend the use of metformin in treating NASH. Similarly, a number of studies showed pioglitazone could exert an inhibitory effect on hepatic steatohepatitis and fibrosis in mice of NAFLD [101][102][103]. But many clinical studies of thiazolidinediones differ with respect to histological and other outcomes.…”

Section: Microbiome-targeted Therapymentioning

confidence: 99%

Rodent Models of Nonalcoholic Fatty Liver Disease

Zhong

Zhou²,

et al. 2019

Digestion

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Background: Nonalcoholic fatty liver disease (NAFLD) is a continuous diseases spectrum associated with obesity, type 2 diabetes, insulin resistance, and hyperlipidemia. Simple hepatic steatosis may progress to nonalcoholic steatohepatitis (NASH), even fibrosis and cirrhosis, and finally hepatocellular carcinoma. In recent years, NAFLD has become a public health concern with increasing prevalence. However, the mechanisms underlying the pathogenesis remain incompletely understood, and few effective therapeutic approaches are available. Summary and Key Messages: A myriad of different rodent models has been developed to elucidate pathophysiology of NAFLD/NASH and guide therapeutic strategy. To date, no single rodent model can display the whole disease spectrum and metabolic features associated with human NASH, but can imitate particular characteristics. In this paper, we review the most commonly used dietary, genetic, and chemical rodent models for NAFLD referring to their advantages and disadvantages. Also, we illustrate the status of latest treatment strategy using various NAFLD rodent models. We hope to provide critical guidance for researchers to select appropriate animal models.

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“…A previous study found that chronic (6 months) pioglitazone treatment suppressed hepatic TCA cycle flux in a rodent model of NASH, attributing the effects to reduced liver lipid accumulation (19). However, no detailed mechanism was identified for the alteration of mitochondrial function by pioglitazone.…”

Section: Discussionmentioning

confidence: 99%

“…Although typically ascribed to adipose tissue PPAR-γ-mediated reductions in systemic lipid concentrations and ectopic lipid accumulation (13–15), the disease-modifying effects of pioglitazone may also involve direct effects on liver metabolism. For example, pioglitazone acutely suppresses glucose production in cultured hepatocytes (16, 17) and perfused livers (18) and was recently found to decrease liver TCA cycle flux in a mouse model of NASH (19). The molecular mechanisms responsible for modulation of hepatic mitochondrial metabolism by pioglitazone are uncertain, but data from our lab (16) and others (20) indicate that they may involve the inhibition of mitochondrial pyruvate fluxes.…”

Section: Introductionmentioning

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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Pioglitazone improves hepatic mitochondrial function in a mouse model of nonalcoholic steatohepatitis

Cited by 55 publications

References 42 publications

Paeoniflorin Ameliorates Fructose-Induced Insulin Resistance and Hepatic Steatosis by Activating LKB1/AMPK and AKT Pathways

Paeoniflorin Ameliorates Fructose-Induced Insulin Resistance and Hepatic Steatosis by Activating LKB1/AMPK and AKT Pathways

Rodent Models of Nonalcoholic Fatty Liver Disease

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

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