Inhibition of mitochondrial fatty acid oxidation in vivo only slightly suppresses gluconeogenesis but enhances clearance of glucose in mice

Derks, Terry G J; Dijk, Theo H. van; Grefhorst, Aldo; Rake, Jan Peter; Smit, Gerrit; Kuipers, Folkert; Reijngoud, Dirk-Jan

doi:10.1002/hep.22101

Cited by 31 publications

(31 citation statements)

References 35 publications

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“…Prior to the infusion experiment, mice were fasted overnight. They were infused with a solution containing [U- 13 C]glucose, [2-13 C]glycerol, [1-2 H]galactose, and paracetamol at an infusion rate of 0.6 ml per hour, as previously described, for 210 minutes (19). Then, the infusion of a second solution containing glucose (1,067 mM) and [U- 13 C] glucose (50 mM) was initiated, while the infusion of the first solution was continued.…”

Section: Methodsmentioning

confidence: 99%

LRH-1–dependent glucose sensing determines intermediary metabolism in liver

Oosterveer¹,

Mataki²,

Yamamoto³

et al. 2012

J. Clin. Invest.

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104

118

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Liver receptor homolog 1 (LRH-1), an established regulator of cholesterol and bile acid homeostasis, has recently emerged as a potential drug target for liver disease. Although LRH-1 activation may protect the liver against diet-induced steatosis and insulin resistance, little is known about how LRH-1 controls hepatic glucose and fatty acid metabolism under physiological conditions. We therefore assessed the role of LRH-1 in hepatic intermediary metabolism. In mice with conditional deletion of Lrh1 in liver, analysis of hepatic glucose fluxes revealed reduced glucokinase (GCK) and glycogen synthase fluxes as compared with those of wild-type littermates. These changes were attributed to direct transcriptional regulation of Gck by LRH-1. Impaired glucokinase-mediated glucose phosphorylation in LRH-1-deficient livers was also associated with reduced glycogen synthesis, glycolysis, and de novo lipogenesis in response to acute and prolonged glucose exposure. Accordingly, hepatic carbohydrate response element-binding protein activity was reduced in these animals. Cumulatively, these data identify LRH-1 as a key regulatory component of the hepatic glucose-sensing system required for proper integration of postprandial glucose and lipid metabolism. IntroductionThe liver plays a central role in metabolic homeostasis by coordinating the synthesis, storage, breakdown, and redistribution of nutrients. Adequate control of these metabolic processes is of importance to accommodate systemic fuel requirements and availability. This is achieved through regulatory complexes that modulate both the catalytic activity and the expression level of metabolic enzymes. While the first usually enables rapid changes in enzymatic activity triggered by allosteric regulation or covalent modification, the second regulatory process is slower and involves transcription factors that adjust gene expression levels. In this context, nuclear receptors and their coregulators have been shown to play a key role in the transcriptional regulation of metabolic enzyme expression in response to changes in cellular nutrient and energy status (1, 2).Liver receptor homolog 1 (LRH-1, also known as NR5A2), a member of the NR5A superfamily of nuclear receptors, is highly expressed in the liver. Hepatic LRH-1 promotes the expression of the bile acid-synthesizing enzymes Cyp7a1 and Cyp8b1 (3-5), while it suppresses acute phase response genes (6, 7). As a consequence, bile acid metabolism is altered in liver-specific LRH-1 knockout mice (3, 4), and LRH-1 heterozygous animals show an exacerbated inflammatory response (6). Other established LRH-1 target genes in the liver are known mediators of hepatic cholesterol uptake and efflux (8, 9), HDL formation (10, 11), cholesterol exchange between lipoproteins (12), and fatty acid synthesis (13). Although these findings point to a broader role for LRH-1 in hepatic lipid metabolism and reverse cholesterol transport, their physiological impact is as yet unknown.

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Section: Methodsmentioning

confidence: 99%

LRH-1–dependent glucose sensing determines intermediary metabolism in liver

Oosterveer¹,

Mataki²,

Yamamoto³

et al. 2012

J. Clin. Invest.

Self Cite

104

118

View full text Add to dashboard Cite

show abstract

“…After recovery, the mice were fasted from 6:00 to 10:00 a.m. Conscious, unrestrained mice were infused with a solution containing [U- 13 C]glucose (7 mM), [2-13 C]glycerol (82 mM), [1-2 H]galactose (17 mM), and paracetamol (1 mg/ml) for 6 h at an infusion rate of 0.6 ml/h as described previously (37). Blood glucose concentrations were measured every 30 min.…”

Section: In Vivo Hepatic Carbohydrate Flux Measurements In C57bl/6mentioning

confidence: 99%

Fenofibrate Simultaneously Induces Hepatic Fatty Acid Oxidation, Synthesis, and Elongation in Mice

Oosterveer

Grefhorst

Dijk

et al. 2009

Journal of Biological Chemistry

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149

135

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A growing body of evidence indicates that peroxisome proliferator-activated receptor ␣ (PPAR␣) not merely serves as a transcriptional regulator of fatty acid catabolism but also exerts a much broader role in hepatic lipid metabolism. We determined adaptations in hepatic lipid metabolism and related aspects of carbohydrate metabolism upon treatment of C57Bl/6 mice with the PPAR␣ agonist fenofibrate. Stable isotope procedures were applied to assess hepatic fatty acid synthesis, fatty acid elongation, and carbohydrate metabolism. Fenofibrate treatment strongly induced hepatic de novo lipogenesis and chain elongation (؎300, 150, and 600% for C16:0, C18:0, and C18:1 synthesis, respectively) in parallel with an increased expression of lipogenic genes. The lipogenic induction in fenofibrate-treated mice was found to depend on sterol regulatory element-binding protein 1c (SREBP-1c) but not carbohydrate response element-binding protein (ChREBP). Fenofibrate treatment resulted in a reduced contribution of glycolysis to acetylCoA production, whereas the cycling of glucose 6-phosphate through the pentose phosphate pathway presumably was enhanced. Altogether, our data indicate that ␤-oxidation and lipogenesis are induced simultaneously upon fenofibrate treatment. These observations may reflect a physiological mechanism by which PPAR␣ and SREBP-1c collectively ensure proper handling of fatty acids to protect the liver against cytotoxic damage.Fatty acids are cytotoxic molecules. Both their oxidation and storage as triglycerides (TGs) 2 may be important in protecting the liver against lipotoxicity. Recently it was postulated that an increased conversion of saturated fatty acids into monounsaturated fatty acids (MUFAs) stimulates storage as TG and prevents non-esterified fatty acid (NEFA)-induced hepatocellular apoptosis (1). However, the mechanisms underlying this lipogenic response have remained enigmatic. Peroxisome proliferator-activated receptors (PPARs) represent likely candidates to mediate this response because these nuclear receptors act as cellular fatty acid sensors.PPAR␣ induces the remodeling of hepatic lipid metabolism under conditions of increased fatty acid influx such as fasting and high fat feeding (2-4). Upon activation, PPAR␣ induces the expression of a multitude of genes encoding proteins involved in peripheral lipid mobilization and fatty acid oxidation (2, 3, 5-7). In addition PPAR␣ plays a role in hepatic lipid droplet formation (8, 9) and mediates adaptive responses to prevent oxidative stress and the accumulation of cytotoxic NEFAs (10). For example, PPAR␣ promotes the degradation of lipid-derived inflammatory mediators (11) and induces mitochondrial uncoupling as well as antioxidant systems to protect against oxidative damage associated with (incomplete) ␤-oxidation (12-18). As a consequence, PPAR␣ activity protects against hepatic inflammation in mice (19 -22).Fibrates are pharmacological PPAR␣ agonists that are used clinically to treat dyslipidemia (23). Interestingly, PPAR␣ agonist treatment has al...

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“…The energy released in the process of -oxidation is -at least in part-used by the liver to carry out de novo glucose production, i.e. gluconeogenesis, from substrates such as glycerol, lactate, and amino acids [19]. In addition, acetyl-CoA derived from FFA -oxidation serves as substrate for the synthesis of ketone bodies that are exported from the liver and used as primary energy source by skeletal muscle or brain after long time starvation [20][21][22][23].…”

Section: Page 4 Of 40mentioning

confidence: 99%

Transcriptional co-factors and hepatic energy metabolism

Sommerfeld

Krones-Herzig

Herzig

2011

Molecular and Cellular Endocrinology

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After binding to their cognate DNA-binding partner, transcriptional co-factors exert their function through the recruitment of enzymatic, chromatin-modifying activities. In turn, the assembly of co-factor-associated multi-protein complexes efficiently impacts target gene expression. Recent advances have established transcriptional co-factor complexes as a critical regulatory level in energy homeostasis and aberrant co-factor activity has been linked to the pathogenesis of severe metabolic disorders including obesity, type 2 diabetes and other components of the Metabolic Syndrome. The liver represents the key peripheral organ for the maintenance of systemic energy homeostasis, and aberrations in hepatic glucose and lipid metabolism have been causally linked to the manifestation of disorders associated with the Metabolic Syndrome. Therefore, this review focuses on the role of distinct classes of transcriptional co-factors in hepatic glucose and lipid homeostasis, emphasizing pathwayspecific functions of these co-factors under physiological and pathophysiological conditions.

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Inhibition of mitochondrial fatty acid oxidation in vivo only slightly suppresses gluconeogenesis but enhances clearance of glucose in mice

Cited by 31 publications

References 35 publications

LRH-1–dependent glucose sensing determines intermediary metabolism in liver

LRH-1–dependent glucose sensing determines intermediary metabolism in liver

Fenofibrate Simultaneously Induces Hepatic Fatty Acid Oxidation, Synthesis, and Elongation in Mice

Transcriptional co-factors and hepatic energy metabolism

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