Lipid Metabolism and Liver Inflammation. II. Fatty liver disease and fatty acid oxidation

Reddy, Janardan K.; Rao, M. Sambasiva

doi:10.1152/ajpgi.00521.2005

Cited by 757 publications

(635 citation statements)

References 29 publications

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“…Analysis using qRT-PCR showed no difference in key transcripts from the major pathways implicated in the development of NAFLD comparing experimental and control animals (Table S1) [31], [32], [33], [34], [35], [36]. To gain further insight into the pathogenesis of NAFLD in the ICD-E mice we therefore examined liver transcription at 6 and 24 hour time points, using expression microarrays.…”

Section: Resultsmentioning

confidence: 99%

Intestinal Activation of Notch Signaling Induces Rapid Onset Hepatic Steatosis and Insulin Resistance

2011

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Here we investigate the effects of expressing an activated mutant of Notch (ICD-E) in an inducible transgenic mouse model. Hepatic expression of ICD-E in adult animals has no detectable phenotype, but simultaneous induction of ICD-E in both the liver and small intestine results in hepatic steatosis, lipogranuloma formation and mild insulin resistance within 96 hours. This supports work that suggests that fatty liver disease may result from disruption of the gut-liver axis. In the intestine, ICD-E expression is known to produce a transient change in the proportion of goblet cells followed by shedding of the recombinant epithelium. We report additional intestinal transcriptional changes following ICD-E expression, finding significant transcriptional down-regulation of rpL29 (ribosomal protein L29), which is implicated in the regulation of intestinal flora. These results provide further evidence of a gut-liver axis in the development of fatty liver disease and insulin resistance and validate a new model for future studies of hepatic steatosis.

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Section: Resultsmentioning

confidence: 99%

Intestinal Activation of Notch Signaling Induces Rapid Onset Hepatic Steatosis and Insulin Resistance

2011

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“…Elevated FAS.. De novo FAS in the liver is regulated by three known transcription factors: steroid regulatory element-binding protein (SREBP-1c) 22 ; carbohydrate response element-binding protein (ChREBP) 23 ; and peroxisome proliferator-activated receptor gamma. 24 Hyperinsulinemia induces hepatic SREBP-1c expression while hyperglycemia stimulates ChREBP activity. These events lead to transcriptional activation of all lipogenic genes including adenosine triphosphate citrate lyase, acetyl-CoA carboxylase, and FAS, 25 effectively increasing FAS flux.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Hyperpolarized Carbon-13 Magnetic Resonance Spectroscopy Reveals Increased Pyruvate Carboxylase Flux in an Insulin-Resistant Mouse Model

et al. 2013

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The pathogenesis of type 2 diabetes is characterized by impaired insulin action and increased hepatic glucose production (HGP). Despite the importance of hepatic metabolic aberrations in diabetes development, there is currently no molecular probe that allows measurement of hepatic gluconeogenic pathways in vivo and in a noninvasive manner. In this study, we used hyperpolarized carbon 13 ( 13 C)-labeled pyruvate magnetic resonance spectroscopy (MRS) to determine changes in hepatic gluconeogenesis in a high-fat diet (HFD)-induced mouse model of type 2 diabetes. Compared with mice on chow diet, HFD-fed mice displayed higher levels of oxaloacetate, aspartate, and malate, along with increased 13 C label exchange rates between hyperpolarized [1-13 C]pyruvate and its downstream metabolites, [1-13 C]malate and [1-13 C]aspartate. Biochemical assays using liver extract revealed up-regulated malate dehydrogenase activity, but not aspartate transaminase activity, in HFD-fed mice. Moreover, the 13 C label exchange rate between [1-13 C]pyruvate and [1-13 C]aspartate (k pyr->asp ) exhibited apparent correlation with gluconeogenic pyruvate carboxylase (PC) activity in hepatocytes. Finally, up-regulated HGP by glucagon stimulation was detected by an increase in aspartate signal and k pyr->asp , whereas HFD mice treated with metformin for 2 weeks displayed lower production of aspartate and malate, as well as reduced k pyr->asp and 13 C-label exchange rate between pyruvate and malate, consistent with down-regulated gluconeogenesis. Conclusion: Taken together, we demonstrate that increased PC flux is an important pathway responsible for increased HGP in diabetes development, and that pharmacologically induced metabolic changes specific to the liver can be detected in vivo with a hyperpolarized 13 C-biomolecular probe. Hyperpolarized 13 C MRS and the determination of metabolite exchange rates may allow longitudinal monitoring of liver function in disease development. (HEPATOLOGY 2013;57:515-524) T he coordinated actions of insulin and glucagon ensure that glucose homeostasis is maintained across a wide range of physiological conditions. In obesity-associated type 2 diabetes, control of glucose metabolism by these two regulatory hormones is impaired, resulting in hepatic insulin resistance and excessive endogenous glucose production. 1 To date, it has not been possible to evaluate this metabolic dysfunction in the liver by a noninvasive in vivo method.Carbon-13 ( 13 C) magnetic resonance spectroscopy (MRS) has been used to study hepatic gluconeogenesis since the 1980s. However, its inherent low sensitivity has largely limited its application to the study of steady-state metabolism in perfused livers with long Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; 13 C, carbon-13; ChREBP, carbohydrate response element-binding protein; FAS, fatty acid synthase; G-6-Pase, glucose-6-phosphatase; HFD, high-fat diet; HGP, hepatic glucose production; IHTG, intrahepatic triglyceride; IPGTT, intraperitoneal glucose toleranc...

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“…Also, EETs and 20-HETE are associated with increased production of reactive oxygen species [19,47], and could contribute to mitochondrial ROS production. Further, P450 aa products can activate PPARα, a regulator of mitochondrial fatty acid oxidation [48,49]. Induction of CYP1A dependent aa metabolism in mitochondria provides a new venue for P450 aa metabolism, one that has significant implications for affecting mitochondrial function.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial P450-dependent arachidonic acid metabolism by TCDD-induced hepatic CYP1A5; conversion of EETs to DHETs by mitochondrial soluble epoxide hydrolase

Labitzke¹,

Diani-Moore²,

Rifkind³

2007

Archives of Biochemistry and Biophysics

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Several P450 enzymes localized in the endoplasmic reticulum and thought to be involved primarily in xenobiotic metabolism, including mouse and rat CYP1A1 and mouse CYP1A2, have also been found to translocate to mitochondria. We report here that the environmental toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces enzymatically active CYP1A4/1A5, the avian orthologs of mammalian CYP1A1/1A2, in chick embryo liver mitochondria as well as in microsomes. P450 proteins and activity levels (CYP1A4-dependent 7-ethoxyresorufin-O-deethylase and CYP1A5-dependent arachidonic acid epoxygenation) in mitochondria were 23-40% of those in microsomes. DHET formation by mitochondria was twice that of microsomes and was attributable to a mitochondrial soluble epoxide hydrolase as confirmed by Western blotting with antiEPHX2, conversion by mitochondria of pure 11,12 and 14,15-EET to the corresponding DHETs and inhibition of DHET formation by the soluble epoxide hydrolase inhibitor, 12(-3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA). TCDD also suppressed formation of mitochondrial and microsomal 20-HETE. The findings newly identify mitochondria as a site of P450-dependent arachidonic acid metabolism and as a potential target for TCDD effects. They also demonstrate that mitochondria contain soluble epoxide hydrolase and underscore a role for CYP1A in endobiotic metabolism.

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Lipid Metabolism and Liver Inflammation. II. Fatty liver disease and fatty acid oxidation

Abstract: Reddy, Janardan K., and M. Sambasiva Rao. Lipid Metabolism and Liver Inflammation. II. Fatty liver disease and fatty acid oxidation.

Cited by 757 publications

References 29 publications

Intestinal Activation of Notch Signaling Induces Rapid Onset Hepatic Steatosis and Insulin Resistance

Intestinal Activation of Notch Signaling Induces Rapid Onset Hepatic Steatosis and Insulin Resistance

In Vivo Hyperpolarized Carbon-13 Magnetic Resonance Spectroscopy Reveals Increased Pyruvate Carboxylase Flux in an Insulin-Resistant Mouse Model

Mitochondrial P450-dependent arachidonic acid metabolism by TCDD-induced hepatic CYP1A5; conversion of EETs to DHETs by mitochondrial soluble epoxide hydrolase

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