Excess consumption of carbohydrates, fat and calories leads to non-alcoholic fatty liver disease (NAFLD) and hepatic insulin resistance; these are major factors in the pathogenesis of type II diabetes. Hormones and catecholamines acting through G-protein coupled receptors (GPCRs) linked to phospholipase C (PLC) and increases in cytosolic Ca2+ ([Ca2+]c) regulate many metabolic functions of the liver. In the intact liver, catabolic hormones such as glucagon, catecholamines and vasopressin integrate and synergize to regulate the frequency and extent to which [Ca2+]c waves propagate across hepatic lobules to control metabolism. Dysregulation of hepatic Ca2+ homeostasis has been implicated in the development of metabolic disease, but changes in hepatic GPCR-dependent Ca2+ signalling have been largely unexplored in this context. We show that short-term, 1-week, high-fat diet (HFD) feeding of mice attenuates noradrenaline-stimulated Ca2+ signalling, reducing the number of cells responding and suppressing the frequency of [Ca2+]c oscillations in both isolated hepatocytes and intact liver. The 1-week HFD feeding paradigm did not change basal Ca2+ homeostasis; endoplasmic reticulum Ca2+ load, store-operated Ca2+ entry and plasma membrane Ca2+ pump activity were unchanged compared to low-fat diet (LFD)-fed controls. However, noradrenaline-induced inositol 1,4,5-trisphosphate production was significantly reduced after HFD feeding, demonstrating an effect of HFD on receptor-stimulated PLC activity. Thus, we have identified a lesion in the PLC signalling pathway induced by short-term HFD feeding, which interferes with hormonal Ca2+ signalling in isolated hepatocytes and the intact liver. These early events may drive adaptive changes in signalling, which lead to pathological consequences in fatty liver disease. Key points Non-alcoholic fatty liver disease (NAFLD) is a growing epidemic. In healthy liver, the counteracting effects of catabolic and anabolic hormones regulate metabolism and energy storage as fat. Hormones and catecholamines promote catabolic metabolism via increases in cytosolic Ca2+ ([Ca2+]c). We show that 1 week high-fat diet (HFD) feeding of mice attenuated the Ca2+ signals induced by physiological concentrations of noradrenaline. Specifically, HFD suppressed the normal pattern of periodic [Ca2+]c oscillations in isolated hepatocytes and disrupted the propagation of intralobular [Ca2+]c waves in the intact perfused liver. Short-term HFD inhibited noradrenaline-induced inositol 1,4,5-trisphosphate generation, but did not change basal endoplasmic reticulum Ca2+ load or plasma membrane Ca2+ fluxes. We propose that impaired Ca2+ signalling plays a key role in the earliest phases of the etiology of NAFLD, and is responsible for many of the ensuing metabolic and related dysfunctional outcomes at the cellular and whole tissue level. 

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1113/JP283691

Short‐term high‐fat diet feeding of mice suppresses catecholamine‐stimulated Ca 2+ signalling in hepatocytes and intact liver

A Tale of two receptors.

Purinergic signaling in liver disease: calcium signaling and induction of inflammation

Abstract Excess consumption of carbohydrates, fat, and calories leads to non-alcoholic fatty liver disease (NAFLD) and hepatic insulin resistance; major factors in the pathogenesis of type II diabetes. Hormones and catecholamines acting through G-protein coupled receptors (GPCRs) linked to phospholipase C (PLC) and increases in cytosolic Ca 2+ ([Ca 2+ ] c ) regulate many metabolic functions of the liver. In the intact liver, catabolic hormones such as glucagon, catecholamines and vasopressin integrate and synergize to regulate the frequency and extent to which [Ca 2+ ] c waves propagate across hepatic lobules to control metabolism. Dysregulation of hepatic Ca 2+ homeostasis has been implicated in the development of metabolic disease, but changes in hepatic GPCR-dependent Ca 2+ signalling have been largely unexplored in this context. We show that short-term, 1-week, high fat diet (HFD) feeding of mice attenuates norepinephrine-stimulated Ca 2+ signalling, reducing the number of cells responding and suppressing the frequency of [Ca 2+ ] c oscillations in both isolated hepatocytes and intact liver. The 1-week HFD feeding paradigm did not change basal Ca 2+ homeostasis; endoplasmic reticulum Ca 2+ load, store-operated Ca 2+ entry and plasma membrane Ca 2+ pump activity were unchanged compared to low fat diet (LFD) fed controls. However, norepinephrine-induced IP 3 production was significantly reduced after HFD feeding, demonstrating an effect of HFD on receptor-stimulated PLC activity. Thus, we have identified a lesion in the PLC signalling pathway induced by short-term HFD feeding, which interferes with hormonal Ca 2+ signalling in isolated hepatocytes and the intact liver. These early events may drive adaptive changes in signalling, which lead to pathological consequences in fatty liver disease. Key points summary Non-alcoholic fatty liver disease (NAFLD) is a growing epidemic. In healthy liver, the counteracting effects of catabolic and anabolic hormones regulate metabolism and energy storage as fat. Hormones and catecholamines promote catabolic metabolism via increases in cytosolic Ca 2+ ([Ca 2+ ] c ). We show that 1 week high fat diet (HFD) feeding of mice attenuated the Ca 2+ signals induced by physiological concentrations of norepinephrine. Specifically, HFD suppressed the normal pattern of periodic [Ca 2+ ] c oscillations in isolated hepatocytes and disrupted the propagation of intralobular [Ca 2+ ] c waves in the intact perfused liver. Short-term HFD inhibited norepinephrine-induced inositol 1,4,5-trisphosphate (IP 3 ) generation, but did not change basal endoplasmic reticulum Ca 2+ load or plasma membrane Ca 2+ fluxes. We propose that impaired Ca 2+ signalling plays a key role in the earliest phases of the etiology of NAFLD, and is responsible for many of the ensuing metabolic and related dysfunctional outcomes at the cellular and whole tissue level. 

Short-term high fat diet feeding of mice suppresses catecholamine-stimulated Ca2+ signalling in hepatocytes and intact liver

Protein kinase D (PKD) emerged as a key node in cellular signaling, but its role in mechanobiology remains unknown. Here, we show that stimulation of the mechanosensitive Piezo1 ion channel markedly increases PKD multisite phosphorylation, indicative of activation. Opening of Piezo1 also promotes histone deacetylase (HDAC)7 phosphorylation and endothelial cell migration in a PKD-dependent manner. The results implicate PKD signaling in the function of Piezo 1 and identify a Piezo1/Ca 2+ /PKC/PKD/HDA7 signaling pathway in endothelial cells. 

Activation of the Piezo1 channel stimulates protein kinase D and migration in human aortic endothelial cells

Extracellular nucleotides are key regulators of liver physiology. In primary rat hepatocytes, P2Y1 receptor (P2Y1R) activation by ADP generates cytosolic calcium ([Ca2+]c) oscillations with narrow spikes, whereas P2Y2/4R activation by UTP led to more complex broad [Ca2+]c oscillations. Both [Ca2+]c oscillation signatures were observed with the common agonist ATP. Inhibition of Gq signaling with YM-254890 abolished ATP-induced [Ca2+]c oscillations, indicating that they depend on inositol 1,4,5-trisphosphate (IP3), and are not mediated by P2X receptors. The narrow P2Y1-linked [Ca2+]c spikes and the broad P2Y2/4-linked [Ca2+]c spikes are shaped by differential and complex PKC-mediated feedback mechanisms. Downregulation of PKC broadened both ADP- and UTP-induced [Ca2+]c oscillations, with a more pronounced effect on the former. PKC downregulation also selectively elicited a more robust response to ADP stimulation, enhancing oscillatory and sustained [Ca2+]c responses. Acute PKC modulation confirmed the importance of the negative PKC feedback regulation of P2Y1R-linked [Ca2+]c signals; such that PKC activation decreased [Ca2+]c oscillation frequency and PKC inhibition increased [Ca2+]c spike width. However, both PKC activation and inhibition decreased the spike width of P2Y2/4R-induced [Ca2+]c oscillations, suggesting that multiple opposing PKC feedback mechanisms shape P2Y2/4R responses. Significantly, plasma membrane Ca2+ entry was required for negative PKC feedback on P2Y1R-linked [Ca2+]c oscillations, whereas P2Y2/4R-linked [Ca2+]c oscillations were less sensitive to negative regulation by PKC and independent of Ca2+ influx. Thus, differential feedback regulation by PKC gives rise to receptor-specific [Ca2+]c oscillation profiles, which can encode the diverse physiological and pathophysiological responses to distinct agonists that all act through the IP3 signaling cascade.

https://biorxiv.org/content/10.1101/2020.10.29.360784v1.full.pdf

Purinergic P2Y1 and P2Y2/4 receptors elicit distinct Ca2+ signaling patterns in hepatocytes via differential feedback regulation by Protein Kinase C

Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are both characterized by an acute insult leading to dysfunction of the liver and often other organs. Acute liver failure is defined by coagulopathy (INR > 1.5) and hepatic encephalopathy in the context of a new hepatic insult within the past 26 weeks [1]. It is relatively rare, with approximately 2000 cases per year diagnosed in the United States [2]. ACLF refers to an acute decompensation of chronic liver disease, but lacks a single clear definition [1]; the definitions used the most in studies discussed herein are reviewed in Table 17.1. Orthotopic liver transplant (OLT) is a valuable therapy for both conditions, but as with chronic liver failure, the demand for organs exceeds the supply. In the absence of liver transplant, the mortality of ALF has been estimated at >80% in some studies [1]. While the inconsistent definition makes ACLF mortality difficult to determine, a review based on the Asian Pacific Association for the Study of the Liver (APASL) and the European Foundation for the Study of Chronic Liver Failure (EASL-CLIF) definitions found a 90-day transplant-free mortality of about 50% [5].

Looking Past Orthotopic Liver Transplantation: A Review of Emerging Strategies for Managing Acute and Acute-on-Chronic Liver Failure

Receptor-specific Ca2+ oscillation patterns mediated by differential regulation of P2Y purinergic receptors in rat hepatocytes

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Purinergic P2Y1 and P2Y2/4 receptors elicit distinct Ca2+ signaling patterns in hepatocytes via differential feedback regulation by Protein Kinase C

Looking Past Orthotopic Liver Transplantation: A Review of Emerging Strategies for Managing Acute and Acute-on-Chronic Liver Failure

Receptor-specific Ca2+ oscillation patterns mediated by differential regulation of P2Y purinergic receptors in rat hepatocytes