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Liver serine palmitoyltransferase activity deficiency in early life impairs adherens junctions and promotes tumorigenesis.

ABSTRACT: Serine palmitoyltransferase is the key enzyme in sphingolipid biosynthesis. Mice lacking serine palmitoyltransferase are embryonic lethal. We prepared liver-specific mice deficient in the serine palmitoyltransferase long chain base subunit 2 gene using an albumin-cyclization recombination approach and found that the deficient mice have severe jaundice. Moreover, the deficiency impairs hepatocyte polarity, attenuates liver regeneration after hepatectomy, and promotes tumorigenesis. Importantly, we show that the deficiency significantly reduces sphingomyelin but not other sphingolipids in hepatocyte plasma membrane; greatly reduces cadherin, the major protein in adherens junctions, on the membrane; and greatly induces cadherin phosphorylation, an indication of its degradation. The deficiency affects cellular distribution of ?-catenin, the central component of the canonical Wnt pathway. Furthermore, such a defect can be partially corrected by sphingomyelin supplementation in vivo and in vitro.The plasma membrane sphingomyelin level is one of the key factors in regulating hepatocyte polarity and tumorigenesis. (Hepatology 2016;64:2089-2102).

SUBMITTER: Li Z

PROVIDER: S-EPMC5115983 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Liver serine palmitoyltransferase activity deficiency in early life impairs adherens junctions and promotes tumorigenesis.

Li Zhiqiang Z Kabir Inamul I Jiang Hui H Zhou Hongwen H Libien Jenny J Zeng Jianying J Stanek Albert A Ou Peiqi P Li Kailyn R KR Zhang Shane S Bui Hai H HH Kuo Ming-Shang MS Park Tae-Sik TS Kim Benjamin B Worgall Tilla S TS Huan Chongmin C Jiang Xian-Cheng XC

Hepatology (Baltimore, Md.) 20161201 6

Serine palmitoyltransferase is the key enzyme in sphingolipid biosynthesis. Mice lacking serine palmitoyltransferase are embryonic lethal. We prepared liver-specific mice deficient in the serine palmitoyltransferase long chain base subunit 2 gene using an albumin-cyclization recombination approach and found that the deficient mice have severe jaundice. Moreover, the deficiency impairs hepatocyte polarity, attenuates liver regeneration after hepatectomy, and promotes tumorigenesis. Importantly, w ...[more]

PMID: 27642075

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Project description:Background & aimsOxidative stress-mediated ferroptosis and macrophage-related inflammation play an important role in various liver diseases. Here, we explored if and how hepatocyte ferroptosis regulates macrophage stimulator of interferon genes (STING) activation in the development of spontaneous liver damage, fibrosis, and tumorigenesis.MethodsWe used a transforming growth factor-beta-activated kinase 1 (TAK1) deficiency-induced model of spontaneous liver damage, fibrosis, and tumorigenesis to investigate hepatocyte ferroptosis and its impact on macrophage STING signalling. Primary hepatocytes and macrophages were used for in vitro experiments.ResultsSignificant liver injury and increased numbers of intrahepatic M1 macrophages were found in hepatocyte-specific TAK1-deficient (TAK1ΔHEP) mice, peaking at 4 weeks and gradually decreasing at 8 and 12 weeks. Meanwhile, activation of STING signalling was observed in livers from TAK1ΔHEP mice at 4 weeks and had decreased at 8 and 12 weeks. Treatment with a STING inhibitor promoted macrophage M2 polarisation and alleviated liver injury, fibrosis, and tumour burden. TAK1 deficiency exacerbated liver iron metabolism in mice with a high-iron diet. Moreover, consistent with the results from single-cell RNA-Seq dataset, TAK1ΔHEP mice demonstrated an increased oxidative response and hepatocellular ferroptosis, which could be inhibited by reactive oxygen species scavenging. Suppression of ferroptosis by ferrostatin-1 inhibited the activation of macrophage STING signalling, leading to attenuated liver injury and fibrosis and a reduced tumour burden. Mechanistically, increased intrahepatic and serum levels of 8-hydroxydeoxyguanosine were detected in TAK1ΔHEP mice, which was suppressed by ferroptosis inhibition. Treatment with 8-hydroxydeoxyguanosine antibody inhibited macrophage STING activation in TAK1ΔHEP mice.ConclusionsHepatocellular ferroptosis-derived oxidative DNA damage promotes macrophage STING activation to facilitate the development of liver injury, fibrosis, and tumorigenesis. Inhibition of macrophage STING may represent a novel therapeutic approach for the prevention of chronic liver disease.Impact and implicationsThe precise mechanism by which hepatocyte ferroptosis regulates macrophage STING activation in the progression of liver damage, fibrosis, and tumorigenesis remains unclear. Herein, we show that deletion of TAK1 in hepatocytes caused oxidative stress-mediated ferroptosis and macrophage-related inflammation in the development of spontaneous liver injury, fibrosis, and hepatocellular carcinoma.

Project description:The loss of mitochondrial function impairs intracellular energy production and potentially results in chronic liver disease. Increasing evidence suggests that mitochondrial dysfunction in hepatocytes contributes to the activation of hepatic stellate cells (HSCs), thereby resulting in hepatic fibrogenesis. High-temperature requirement protein A2 (HtrA2/Omi), a mitochondrial serine protease with various functions, is responsible for quality control in mitochondrial homeostasis. However, little information is available regarding its role in mitochondrial damage during the development of liver fibrosis. This study examined whether HtrA2/Omi regulates mitochondrial homeostasis in hepatocyte during the development of hepatic fibrogenesis. In this study, we demonstrated that HtrA2/Omi expression considerably decreased in liver tissues from the CCl4-induced liver fibrotic mice model and from patients with liver cirrhosis. Knockdown of HtrA2/Omi in hepatocytes induced the accumulation of damaged mitochondria and provoked mitochondrial reactive oxygen species (mtROS) stress. We further show that the damaged mtDNA isolated from HtrA2/Omi-deficient hepatocytes as a form of damage-associated molecular patterns can induce HSCs activation. Moreover, we found that motor neuron degeneration 2-mutant mice harboring the missense mutation Ser276Cys in the protease domain of HtrA2/Omi displayed altered mitochondrial morphology and function, which increased oxidative stress and promoted liver fibrosis. Conversely, the overexpression of HtrA2/Omi via hydrodynamics-based gene transfer led to the antifibrotic effects in CCl4-induced liver fibrosis mice model through decreasing collagen accumulation and enhancing anti-oxidative activity by modulating mitochondrial homeostasis in the liver. These results suggest that suppressing HtrA2/Omi expression promotes hepatic fibrogenesis via modulating mtROS generation, and these novel mechanistic insights involving the regulation of mitochondrial homeostasis by HtrA2/Omi may be of importance for developing new therapeutic strategies for hepatic fibrosis.

Dataset Information

Liver serine palmitoyltransferase activity deficiency in early life impairs adherens junctions and promotes tumorigenesis.

Publications

Liver serine palmitoyltransferase activity deficiency in early life impairs adherens junctions and promotes tumorigenesis.

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