Lysophosphatidylcholine acyltransferase 1 is downregulated by hepatitis C virus: impact on production of lipo-viro-particles

ObjectiveHCV is intimately linked with the liver lipid metabolism, devoted to the efflux of triacylglycerols stored in lipid droplets (LDs) in the form of triacylglycerol-rich very-low-density lipoproteins (VLDLs): (i) the most infectious HCV particles are those of lowest density due to association with triacylglycerol-rich lipoproteins and (ii) HCV-infected patients frequently develop hepatic steatosis (increased triacylglycerol storage). The recent identification of lysophosphatidylcholine acyltransferase 1 (LPCAT1) as an LD phospholipid-remodelling enzyme prompted us to investigate its role in liver lipid metabolism and HCV infectious cycle.DesignHuh-7.5.1 cells and primary human hepatocytes (PHHs) were infected with JFH1-HCV. LPCAT1 depletion was achieved by RNA interference. Cells were monitored for LPCAT1 expression, lipid metabolism and HCV production and infectivity. The density of viral particles was assessed by isopycnic ultracentrifugation.ResultsUpon HCV infection, both Huh-7.5.1 cells and PHH had decreased levels of LPCAT1 transcript and protein, consistent with transcriptional downregulation. LPCAT1 depletion in either naive or infected Huh-7.5.1 cells resulted in altered lipid metabolism characterised by LD remodelling, increased triacylglycerol storage and increased secretion of VLDL. In infected Huh-7.5.1 cells or PHH, LPCAT1 depletion increased production of the viral particles of lowest density and highest infectivity.ConclusionsWe have identified LPCAT1 as a modulator of liver lipid metabolism downregulated by HCV, which appears as a viral strategy to increase the triacylglycerol content and hence infectivity of viral particles. Targeting this metabolic pathway may represent an attractive therapeutic approach to reduce both the viral titre and hepatic steatosis.

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Dysregulated liver lipid metabolism and innate immunity associated with hepatic steatosis in neonatal BBdp rats and NOD mice

Scientific Reports ◽

10.1038/s41598-019-51143-7 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

D. Serrano ◽

J. A. Crookshank ◽

B. S. Morgan ◽

R. W. Mueller ◽

M.-F. Paré ◽

...

Keyword(s):

Innate Immunity ◽

Lipid Metabolism ◽

Hepatic Steatosis ◽

Liver Lipid ◽

Nod Mice ◽

Gene Signature ◽

Enhanced Expression ◽

Liver Lipid Metabolism ◽

Hepatic Innate Immunity ◽

Lipid Metabolism Genes

Abstract In a previous study we reported that prediabetic rats have a unique gene signature that was apparent even in neonates. Several of the changes we observed, including enhanced expression of pro-inflammatory genes and dysregulated UPR and metabolism genes were first observed in the liver followed by the pancreas. In the present study we investigated further early changes in hepatic innate immunity and metabolism in two models of type 1 diabetes (T1D), the BBdp rat and NOD mouse. There was a striking increase in lipid deposits in liver, particularly in neonatal BBdp rats, with a less striking but significant increase in neonatal NOD mice in association with dysregulated expression of lipid metabolism genes. This was associated with a decreased number of extramedullary hematopoietic clusters as well as CD68+ macrophages in the liver of both models. In addition, PPARɣ and phosphorylated AMPKα protein were decreased in neonatal BBdp rats. BBdp rats displayed decreased expression of antimicrobial genes in neonates and decreased M2 genes at 30 days. This suggests hepatic steatosis could be a common early feature in development of T1D that impacts metabolic homeostasis and tolerogenic phenotype in the prediabetic liver.

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Hepatic Lipidomics Reveals the Homeostasis and Profile of Sphingomyelin from Yak Butter in Normal-Fat Diet-Fed Rats

10.21203/rs.3.rs-118802/v1 ◽

2020 ◽

Author(s):

Xin LUO ◽

Wancheng SUN ◽

Yihao LUO

Keyword(s):

Lipid Metabolism ◽

Hepatic Steatosis ◽

Metabolic Pathways ◽

High Fat Diet ◽

Liver Lipid ◽

Normal Diet ◽

Inflammatory Factors ◽

Tnf Α ◽

Liver Lipid Metabolism ◽

Ifn Γ

Abstract Background: Dietary sphingomyelin was showed to inhibit the uptake of lipids in mice fed with a high-fat diet, however, the effect of sphingomyelin on normal diet was on reported. The current study aims to examine the effects of sphingomyelin extracts from yak butter on hepatic steatosis and inflammation in C57/B6J mice fed with a normal diet. Methods: A UHPLC-QTOF-MS based lipidomics method was utilized to screen the liver metabolites and predict the dominant potential metabolic pathways after sphingomyelin feeding. Results: The results showed that sphingomyelin extracts reduced the accumulation of lipid droplets, suppressed the expression of pro-inflammatory factors IFN -γ, IL-6 and TNF - α, synchronously, promoted the expression of anti-inflammatory factors IL-10, IL-4 and IL-1Ra. In addition, sphingomyelin extracts exhibited the modulation on liver lipid metabolism when supplement sphingomyelin in normal diet for one month and five months. Specifically, 16, 68 different metabolites and 2, 6 metabolic pathways were identified by quantitative lipidomics, respectively. Six CERs including Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d17:1/22:0), Cer(d17:1/24:1), Cer(d17:1/24:0) and Cer(d17:0/26:1), six SMs including SM(d15:0/24:1), SM(d14:0/26:1), SM(d14:1/24:1), SM(d15:1/22:0), SM(d15:1/24:1) and SM(d19:1/26:1), and PS(18:1/22:6) were identified and can be used as potential biomarkers of steatosis and inflammation.Conclusions: This study highlighted the effects of yak butter sphingomyelin on hepatic steatosis, tissue inflammation and lipid metabolism of mice under a normal diet.

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Hepatic Steatosis as a Result of Altered Lipid Metabolism in Mice with Adipocyte-specific Fatp4-deficiency under High-fat Diet

Zeitschrift für Gastroenterologie ◽

10.1055/s-0030-1269568 ◽

2011 ◽

Vol 49 (01) ◽

Author(s):

LS Lenz ◽

J Marx ◽

W Chamulitrat ◽

I Kaiser ◽

HJ Gröne ◽

...

Keyword(s):

Lipid Metabolism ◽

Hepatic Steatosis ◽

High Fat Diet ◽

High Fat ◽

Altered Lipid Metabolism ◽

Altered Lipid

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Hedgehog signaling is a potent regulator of liver lipid metabolism and reveals a GLI-code associated with steatosis

eLife ◽

10.7554/elife.13308 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 34

Author(s):

Madlen Matz-Soja ◽

Christiane Rennert ◽

Kristin Schönefeld ◽

Susanne Aleithe ◽

Jan Boettger ◽

...

Keyword(s):

Transcription Factors ◽

Lipid Metabolism ◽

Liver Disease ◽

Hepatic Steatosis ◽

Hedgehog Signaling ◽

Liver Lipid ◽

Hedgehog Pathway ◽

Alcoholic Fatty Liver ◽

Adult Mice ◽

Liver Lipid Metabolism

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries and is increasing in prevalence. The pathomechanisms, however, are poorly understood. This study assessed the unexpected role of the Hedgehog pathway in adult liver lipid metabolism. Using transgenic mice with conditional hepatocyte-specific deletion of Smoothened in adult mice, we showed that hepatocellular inhibition of Hedgehog signaling leads to steatosis by altering the abundance of the transcription factors GLI1 and GLI3. This steatotic 'Gli-code' caused the modulation of a complex network of lipogenic transcription factors and enzymes, including SREBP1 and PNPLA3, as demonstrated by microarray analysis and siRNA experiments and could be confirmed in other steatotic mouse models as well as in steatotic human livers. Conversely, activation of the Hedgehog pathway reversed the "Gli-code" and mitigated hepatic steatosis. Collectively, our results reveal that dysfunctions in the Hedgehog pathway play an important role in hepatic steatosis and beyond.

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Chronic alcohol exposure alters circulating insulin and ghrelin levels: role of ghrelin in hepatic steatosis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00334.2018 ◽

2019 ◽

Vol 316 (4) ◽

pp. G453-G461 ◽

Cited By ~ 5

Author(s):

Karuna Rasineni ◽

Paul G. Thomes ◽

Jacy L. Kubik ◽

Edward N. Harris ◽

Kusum K. Kharbanda ◽

...

Keyword(s):

Adipose Tissue ◽

Insulin Secretion ◽

Lipid Metabolism ◽

Fatty Liver ◽

Pancreatic Islets ◽

Hepatic Steatosis ◽

Liver Tissue ◽

Serum Ghrelin ◽

Altered Lipid Metabolism ◽

Altered Lipid

Fatty liver is the earliest response of the liver to excessive ethanol consumption. Central in the development of alcoholic steatosis is increased mobilization of nonesterified free fatty acids (NEFAs) to the liver from the adipose tissue. In this study, we hypothesized that ethanol-induced increase in ghrelin by impairing insulin secretion, could be responsible for the altered lipid metabolism observed in adipose and liver tissue. Male Wistar rats were fed for 5–8 wk with control or ethanol Lieber-DeCarli diet, followed by biochemical analyses in serum and liver tissues. In addition, in vitro studies were conducted on pancreatic islets isolated from experimental rats. We found that ethanol increased serum ghrelin and decreased serum insulin levels in both fed and fasting conditions. These results were corroborated by our observations of a significant accumulation of insulin in pancreatic islets of ethanol-fed rats, indicating that its secretion was impaired. Furthermore, ethanol-induced reduction in circulating insulin was associated with lower adipose weight and increased NEFA levels observed in these rats. Additionally, we found that increased concentration of serum ghrelin was due to increased synthesis and maturation in the stomach of the ethanol-fed rats. We also report that in addition to its effect on the pancreas, ghrelin can also directly act on hepatocytes via the ghrelin receptors and promote fat accumulation. In conclusion, alcohol-induced elevation of circulating ghrelin levels impairs insulin secretion. Consequently, reduced circulating insulin levels likely contribute to increased free fatty acid mobilization from adipose tissue to liver, thereby contributing to hepatic steatosis. NEW & NOTEWORTHY Our studies are the first to report that ethanol-induced increases in ghrelin contribute to impaired insulin secretion, which results in the altered lipid metabolism observed in adipose and liver tissue in the setting of alcoholic fatty liver disease.

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Loss of RNF43/ZNRF3 predisposes to Hepatocellular carcinoma by impairing liver regeneration and altering liver fat metabolism

10.1101/2020.09.25.313205 ◽

2020 ◽

Author(s):

Gianmarco Mastrogiovanni ◽

Clare Pacini ◽

Sofia Kakava ◽

Robert Arnes-Benito ◽

Charles R Bradshaw ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Lipid Metabolism ◽

Liver Cancer ◽

Liver Regeneration ◽

Liver Lipid ◽

Liver Fat ◽

Chronic Liver Damage ◽

Hepatocyte Regeneration ◽

Altered Lipid Metabolism ◽

Altered Lipid

The homologous E3 ubiquitin ligases RNF43/ZNRF3 negatively regulate WNT signalling activation. Recently, both genes have been found mutated in several types of cancers. Specifically, loss-of-function mutations result in adenoma formation in mouse small intestine. However, their role in liver cancer has not been explored yet. Here we describe that hepatocyte-specific deletion of both Rnf43/Znrf3 results in altered lipid metabolism and a non-alcoholic steatohepatitis (NASH) phenotype in mouse, in the absence of exogenous fat supplementation. The effect is cell-autonomous, as evidenced by the intracellular lipid accumulation detected in mutant liver organoids. Upon chronic liver damage, Rnf43/Znrf3 deletion results in impaired hepatocyte regeneration, subsequent to an imbalance between hepatocyte differentiation and proliferation, which leads to hepatocellular carcinoma. Remarkably, hepatocellular carcinoma patients with mutations in ZNRF3 also present altered lipid metabolism and poorer survival. Our findings imply that Wnt activation through the RNF43/ZNRF3 module predisposes to liver cancer by altering the liver lipid metabolic ground-state and impairing liver regeneration, which combined, facilitate the progression towards malignancy. Our results highlight the requirement for personalized therapeutic or dietary interventions for those RNF43/ZNRF3 mutated individuals at risk of developing steatosis, NASH and/or liver cancer.

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Circulating Levels of Pro-Neurotensin and Its Relationship with Nonalcoholic Steatohepatitis and Hepatic Lipid Metabolism

Metabolites ◽

10.3390/metabo11060373 ◽

2021 ◽

Vol 11 (6) ◽

pp. 373

Author(s):

Beatriz Villar ◽

Laia Bertran ◽

Carmen Aguilar ◽

Jessica Binetti ◽

Salomé Martínez ◽

...

Keyword(s):

Lipid Metabolism ◽

Nonalcoholic Steatohepatitis ◽

Liver Lipid ◽

Normal Liver ◽

Normal Weight ◽

Published Data ◽

Mrna Levels ◽

Nonalcoholic Fatty Liver ◽

Hepatic Expression ◽

Liver Lipid Metabolism

Recent studies suggest a link between pro-neurotensin (pro-NT) and nonalcoholic fatty liver disease (NAFLD), but the published data are conflicting. Thus, we aimed to analyze pro-NT levels in women with morbid obesity (MO) and NAFLD to investigate if this molecule is involved in NAFLD and liver lipid metabolism. Plasma levels of pro-NT were determined in 56 subjects with MO and 18 with normal weight (NW). All patients with MO were subclassified according to their liver histology into the normal liver (NL, n = 20) and NAFLD (n = 36) groups. The NAFLD group had 17 subjects with simple steatosis (SS) and 19 with nonalcoholic steatohepatitis (NASH). We used a chemiluminescence sandwich immunoassay to quantify pro-NT in plasma and RT-qPCR to evaluate the hepatic mRNA levels of several lipid metabolism-related genes. We reported that pro-NT levels were significantly higher in MO with NAFLD than in MO without NAFLD. Additionally, pro-NT levels were higher in NASH patients than in NL. The hepatic expression of lipid metabolism-related genes was found to be altered in NAFLD, as previously reported. Additionally, although pro-NT levels correlated with LDL, there was no association with the main lipid metabolism-related genes. These findings suggest that pro-NT could be related to NAFLD progression.

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Prenatal hyperandrogenism induces alterations that affect liver lipid metabolism

Journal of Endocrinology ◽

10.1530/joe-15-0471 ◽

2016 ◽

Vol 230 (1) ◽

pp. 67-79 ◽

Cited By ~ 16

Author(s):

Giselle Adriana Abruzzese ◽

Maria Florencia Heber ◽

Silvana Rocio Ferreira ◽

Leandro Martin Velez ◽

Roxana Reynoso ◽

...

Keyword(s):

Metabolic Syndrome ◽

Lipid Metabolism ◽

Glucose Tolerance ◽

Fatty Liver ◽

Lipid Content ◽

Liver Lipid ◽

Acid Oxidation ◽

Liver Lipid Content ◽

Increased Risk ◽

Liver Lipid Metabolism

Prenatal hyperandrogenism is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). PCOS patients have high risk of developing fatty liver and steatosis. This study aimed to evaluate the role of prenatal hyperandrogenism in liver lipid metabolism and fatty liver development. Pregnant rats were hyperandrogenized with testosterone. At pubertal age, the prenatally hyperandrogenized (PH) female offspring displayed both ovulatory (PHov) and anovulatory (PHanov) phenotypes that mimic human PCOS features. We evaluated hepatic transferases, liver lipid content, the balance between lipogenesis and fatty acid oxidation pathway, oxidant/antioxidant balance and proinflammatory status. We also evaluated the general metabolic status through growth rate curve, basal glucose and insulin levels, glucose tolerance test, HOMA-IR index and serum lipid profile. Although neither PH group showed signs of liver lipid content, the lipogenesis and fatty oxidation pathways were altered. The PH groups also showed impaired oxidant/antioxidant balance, a decrease in the proinflammatory pathway (measured by prostaglandin E2 and cyclooxygenase-2 levels), decreased glucose tolerance, imbalance of circulating lipids and increased risk of metabolic syndrome. We conclude that prenatal hyperandrogenism generates both PHov and PHanov phenotypes with signs of liver alterations, imbalance in lipid metabolism and increased risk of developing metabolic syndrome. The anovulatory phenotype showed more alterations in liver lipogenesis and a more impaired balance of insulin and glucose metabolism, being more susceptible to the development of steatosis.

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