Succinate is a paracrine signal for liver damage

Correa, Paulo Renato A.V.; Kruglov, Emma A.; Thompson, Mayerson; Leite, M. Fátima; Dranoff, Jonathan A.; Nathanson, Michael H.

doi:10.1016/j.jhep.2007.03.016

Cited by 135 publications

(149 citation statements)

References 29 publications

(17 reference statements)

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“…Interestingly, succinate has been known for many years to increase in tissues during hypoxia (9)(10)(11) and may act as a surrogate marker for reduced oxygenation. Accordingly, Sucnr1 may be activated in times of hypoxic stress such as ischemic injury in liver (12) or retina (13) or during cardiomyocyte crisis (14). Moreover, dysregulated metabolism, akin to diabetes or the metabolic syndrome, also has the potential to increase peripheral blood concentrations of succinate to levels where activation of the Sucnr1 receptor will occur (15,16).…”

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confidence: 99%

Targeted Disruption of the SUCNR1 Metabolic Receptor Leads to Dichotomous Effects on Obesity

et al. 2014

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A number of metabolites have signaling properties by acting through G-protein-coupled receptors. Succinate, a Krebs cycle intermediate, increases after dysregulated energy metabolism and can bind to its cognate receptor succinate receptor 1 (Sucnr1, or GPR91) to activate downstream signaling pathways. We show that Sucnr1 is highly expressed in the white adipose tissue (WAT) compartment of mice and regulates adipose mass and glucose homeostasis. Sucnr1 2/2 mice were generated, and weight gain was monitored under basal and nutritional stress (high-fat diet [HFD]) conditions. On chow diet, Sucnr1 2/2 mice had increased energy expenditure, were lean with a smaller WAT compartment, and had improved glucose buffering. Lipolysis measurements revealed that Sucnr1 2/2 mice were released from succinate-induced inhibition of lipolysis, demonstrating a function of Sucnr1 in adipose tissue. Sucnr1 deletion also protected mice from obesity on HFD, but only during the initial period; at later stages, body weight of HFD-fed Sucnr1 2/2 mice was almost comparable with wild-type (WT) mice, but WAT content was greater. Also, these mice became progressively hyperglycemic and failed to secrete insulin, although pancreas architecture was similar to WT mice. These findings suggest that Sucnr1 is a sensor for dietary energy and raise the interesting possibility that protocols to modulate Sucnr1 might have therapeutic utility in the setting of obesity.

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Targeted Disruption of the SUCNR1 Metabolic Receptor Leads to Dichotomous Effects on Obesity

et al. 2014

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“…Interestingly, succinate does not inhibit the production of cAMP induced by forskolin neither increase Ca 2+ in quiescent hepatic stellate cells (HSC), where SUCNR1 is present, both at the protein and mRNA level (Correa et al, 2007). However succinate accelerates activation of ischemic HSC, through upregulation of α-smooth muscle actin (α-SMA), a marker of myofibroblastic trans-differentiation (Fig.…”

Section: Ischemia/reperfusion Injurymentioning

confidence: 99%

“…In the liver, although succinate levels significantly increase following ischemia, neither succinate nor glucose are able to increase hepatic perfusion pressure when infused into the portal vein (Correa et al, 2007). Interestingly, succinate does not inhibit the production of cAMP induced by forskolin neither increase Ca 2+ in quiescent hepatic stellate cells (HSC), where SUCNR1 is present, both at the protein and mRNA level (Correa et al, 2007).…”

Section: Ischemia/reperfusion Injurymentioning

confidence: 99%

“…3). Stimulation of SUCNR1 probably potentiates the effects of growth factors and hormones, and by non-traditional signals such as matrix stiffness or oxidant stress that are known to induce stellate cell activation (Correa et al, 2007). Upon activation of HSC, the expression of SUCNR1 in these cells decreases rapidly, suggesting that SUCNR1 serves as an early detector of hepatic stress or damage.…”

Section: Ischemia/reperfusion Injurymentioning

confidence: 99%

“…Upon activation of HSC, the expression of SUCNR1 in these cells decreases rapidly, suggesting that SUCNR1 serves as an early detector of hepatic stress or damage. SUCNR1 signaling plays an enhancing role in HSC activation to restore damaged tissues in the ischemic liver, but may also contribute to the formation of fibrosis (Correa et al, 2007;Y.H. Li, Woo, Choi, & Cho, 2015).…”

Section: Ischemia/reperfusion Injurymentioning

confidence: 99%

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Insight into SUCNR1 (GPR91) structure and function

Gilissen

Jouret

Pirotte

et al. 2016

Pharmacology & Therapeutics

103

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SUCNR1 (or GPR91) belongs to the family of G protein-coupled receptors (GPCR), which represents the largest group of membrane proteins in human genome. The majority of marketed drugs targets GPCRs, directly or indirectly. SUCNR1 has been classified as an orphan receptor until a landmark study paired it with succinate, a citric acid cycle intermediate.According to the current paradigm, succinate triggers SUCNR1 signaling pathways to indicate local stress that may affect cellular metabolism. SUCNR1 implication has been well documented in renin-induced hypertension, ischemia/reperfusion injury, inflammation and immune response, platelet aggregation and retinal angiogenesis. In addition, the SUCNR1-induced increase of blood pressure may contribute to diabetic nephropathy or cardiac hypertrophy.The understanding of SUCNR1 activation, signaling pathways and functions remains largely elusive, which calls for deeper investigations. SUCNR1 shows a high potential as an innovative drug target and is probably an important regulator of basic physiology. In order to achieve the full characterization of this receptor, more specific pharmacological tools such as small-molecules modulators will represent an important asset. In this review, we describe the structural features of SUCNR1, its current ligands and putative binding pocket. We give an exhaustive overview of the known and hypothetical signaling partners of the receptor in different in vitro and in vivo systems. The link between SUCNR1 intracellular pathways and its pathophysiological roles are also extensively discussed.

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Conjugate of pyrimidine derivative, the drug xymedon with succinic acid protects liver cells

Vyshtakalyuk

Парфенов

Gumarova

et al. 2020

J Biochem & Molecular Tox

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The aim of the study was to investigate the hepatoprotective properties of the conjugate of the xymedon drug substance with succinic acid (1a). The study presents an in vitro comparative evaluation of the cytotoxicity and cytoprotective properties of 1a and succinic acid on a cell line of normal human hepatocytes Chang Liver, and in vivo investigation of the ability of 1a to restore liver from the toxic damage caused by CCl4 in Wistar rats. It was shown that the cytotoxicity of 1a was 19.9 ± 0.8 mmol/L, and that of succinic acid was 14.1 ± 0.2 mmol/L. Against the background of d‐galactosamine exposure, the cytoprotective effect of 1a was found to be superior to that of succinic acid. It was shown that 1a caused a significant reduction in necrotic and steatosis changes in the liver and restoration of biochemical markers of cytolysis, as well as bilirubin metabolism and synthetic liver function.

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Succinate is a paracrine signal for liver damage

Abstract: SUMMARYBackground and Aims: A G-protein coupled succinate receptor has recently been identified in several tissues, including the liver. The objectives of this work were to determine the hepatic cell types that express this receptor and to determine its physiological role.

Cited by 135 publications

References 29 publications

Targeted Disruption of the SUCNR1 Metabolic Receptor Leads to Dichotomous Effects on Obesity

Targeted Disruption of the SUCNR1 Metabolic Receptor Leads to Dichotomous Effects on Obesity

Insight into SUCNR1 (GPR91) structure and function

Conjugate of pyrimidine derivative, the drug xymedon with succinic acid protects liver cells

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