Lack of mitochondria-generated acetyl-CoA by pyruvate dehydrogenase complex downregulates gene expression in the hepatic de novo lipogenic pathway

Mahmood, Saleh; Birkaya, Barbara; Rideout, Todd C; Patel, Mulchand S.

doi:10.1152/ajpendo.00064.2016

Cited by 18 publications

(27 citation statements)

References 47 publications

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“…4E) implies that such alternate sources of this intermediate most likely do not exist. Our findings disagree with a recent report showing that KO livers have normal AcCoA levels (32), though that report also did not identify an alternative AcCoA source. This discrepancy most likely relates to the methods for AcCoA detection, i.e.…”

Section: Discussioncontrasting

confidence: 99%

Genetic Dissociation of Glycolysis and the TCA Cycle Affects Neither Normal nor Neoplastic Proliferation

et al. 2017

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Rapidly proliferating cells increase glycolysis at the expense of oxidative phosphorylation (oxphos) to generate sufficient levels of glycolytic intermediates for use as anabolic substrates. The pyruvate dehydrogenase complex (PDC) is a critical mitochondrial enzyme that catalyzes pyruvate’s conversion to acetyl coenzyme A (AcCoA), thereby connecting these two pathways in response to complex energetic, enzymatic and metabolic cues. Here we utilized a mouse model of hepatocyte-specific PDC inactivation to determine the need for this metabolic link during normal hepatocyte regeneration and malignant transformation. In PDC “knockout” (KO) animals, the long-term regenerative potential of hepatocytes was unimpaired, and growth of aggressive experimental hepatoblastomas (HB) was only modestly slowed in the face of 80–90% reductions in AcCoA and significant alterations in the levels of key TCA cycle intermediates and amino acids. Overall, oxphos activity in KO livers and HB was comparable to that of control counterparts, with evidence that metabolic substrate abnormalities were compensated for by increased mitochondrial mass. These findings demonstrate that the biochemical link between glycolysis and the TCA cycle can be completely severed without affecting normal or neoplastic proliferation, even under the most demanding circumstances.

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Section: Discussioncontrasting

confidence: 99%

Genetic Dissociation of Glycolysis and the TCA Cycle Affects Neither Normal nor Neoplastic Proliferation

et al. 2017

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“…The GL/FFA cycle is thought to be central for the generation of lipid-signaling molecules as metabolic coupling factors [19]. Moreover, glucose-derived acetyl-CoA via citrate/pyruvate cycle provides building blocks for the de novo synthesis of fatty acid [24,25]. In our study, high glucose increased the expression of fatty acid synthase, which is involved in the lipogenesis process.…”

Section: Discussionsupporting

confidence: 51%

Berberine inhibits glucose oxidation and insulin secretion in rat islets

et al. 2018

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Abstract. Glucose promotes insulin secretion primarily via its metabolism and the production of metabolic coupling factors in beta-cells. The activation of AMP-activated protein kinase (AMPK), an energy sensor, results in a decrease in insulin secretion from beta-cells, but its mechanism remains largely unknown. Berberine, an oral anti-diabetic drug, has been shown to activate AMPK in multiple peripheral tissues. Here, we examined the effects of berberine and AMPK activation on insulin secretion and glucose oxidation in rat islets. Our results showed that berberine inhibited glucose-stimulated insulin secretion from rat islets with AMPK activation. When glucose concentration was elevated to 25 mmol/L, the inhibitory action of berberine on insulin secretion disappeared. Furthermore, berberine significantly decreased oxygen consumption rate (OCR) and ATP production induced by high glucose in rat islets. Although adenovirus-mediated overexpression of constituentactivated AMPK markedly decreased GSIS and OCR in rat islets, the inhibition of AMPK by compound C did not reverse berberine-suppressed OCR. In addition, berberine attenuated glucose-stimulated expression of fatty acid synthase. These results indicate that berberine-mediated deceleration of glucose oxidation is tightly link to the decreased insulin secretion in islets independent of AMPK activation and inhibition of fatty acid synthesis may also contribute to the effect of berberine on insulin secretion.

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“…Under fed conditions, the liver stores excess glucose as glycogen and converts the fatty acids into triglycerol for export, with very low density lipoproteins. The reduced PDC-generated acetyl-CoA in the liver is a prerequisite for blockade of the de novo lipogenic pathway, which is simultaneously compensated by stimulating lipogenic genes in adipose tissue to maintain the hepatic acetyl-CoA content, independent of hyperinsulinemia with lower blood glucose in liver-specific PDC deficiency [ 43 ]. Generally, SIRTs 1-3 carry a robust lysine deacetylase domain, while SIRT 4-5 display little to no deacetylation activity, especially the mitochondrial SIRT4.…”

Section: Regulation Of Pdc In Different Organsmentioning

confidence: 99%

Role of the Pyruvate Dehydrogenase Complex in Metabolic Remodeling: Differential Pyruvate Dehydrogenase Complex Functions in Metabolism

et al. 2018

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Mitochondrial dysfunction is a hallmark of metabolic diseases such as obesity, type 2 diabetes mellitus, neurodegenerative diseases, and cancers. Dysfunction occurs in part because of altered regulation of the mitochondrial pyruvate dehydrogenase complex (PDC), which acts as a central metabolic node that mediates pyruvate oxidation after glycolysis and fuels the Krebs cycle to meet energy demands. Fine-tuning of PDC activity has been mainly attributed to post-translational modifications of its subunits, including the extensively studied phosphorylation and de-phosphorylation of the E1α subunit of pyruvate dehydrogenase (PDH), modulated by kinases (pyruvate dehydrogenase kinase [PDK] 1-4) and phosphatases (pyruvate dehydrogenase phosphatase [PDP] 1-2), respectively. In addition to phosphorylation, other covalent modifications, including acetylation and succinylation, and changes in metabolite levels via metabolic pathways linked to utilization of glucose, fatty acids, and amino acids, have been identified. In this review, we will summarize the roles of PDC in diverse tissues and how regulation of its activity is affected in various metabolic disorders.

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Lack of mitochondria-generated acetyl-CoA by pyruvate dehydrogenase complex downregulates gene expression in the hepatic de novo lipogenic pathway

Abstract: Mahmood S, Birkaya B, Rideout TC, Patel MS. Lack of mitochondria-generated acetyl-CoA by pyruvate dehydrogenase complex downregulates gene expression in the hepatic de novo lipogenic pathway.

Cited by 18 publications

References 47 publications

Genetic Dissociation of Glycolysis and the TCA Cycle Affects Neither Normal nor Neoplastic Proliferation

Genetic Dissociation of Glycolysis and the TCA Cycle Affects Neither Normal nor Neoplastic Proliferation

Berberine inhibits glucose oxidation and insulin secretion in rat islets

Role of the Pyruvate Dehydrogenase Complex in Metabolic Remodeling: Differential Pyruvate Dehydrogenase Complex Functions in Metabolism

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