Genomics of human fatty liver disease reveal mechanistically linked lipid droplet–associated gene regulations in bland steatosis and nonalcoholic steatohepatitis

Sahini, Nishika; Borlak, Jürgen

doi:10.1016/j.trsl.2016.06.003

Cited by 32 publications

(23 citation statements)

References 156 publications

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“…We identified dilauroylphosphatidylcholine (DLPC), an unusual PC species with two saturated 12-carbon fatty acid acyl chains, as an exogenous LRH-1 agonist and showed that DLPC treatment could attenuate fatty liver and improve insulin sensitivity by repressing lipogenesis. (4) In the opposite direction, LRH-1 mRNA expression is strongly decreased in livers of human subjects with steatosis or nonalcoholic steatohepatitis, (10) and a recent report confirms that acute knockout (KO) of LRH-1 in mouse liver disrupts lipid metabolism and induces fat accumulation. (11) Another report identifying glucokinase as a primary LRH-1 target links LRH-1 to glucose use and glycogen synthesis.…”

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confidence: 93%

Methyl‐Sensing Nuclear Receptor Liver Receptor Homolog‐1 Regulates Mitochondrial Function in Mouse Hepatocytes

et al. 2019

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Background and Aims Liver receptor homolog‐1 (LRH‐1; NR5A2) is a nuclear receptor that regulates metabolic homeostasis in the liver. Previous studies identified phosphatidylcholines as potential endogenous agonist ligands for LRH‐1. In the liver, distinct subsets of phosphatidylcholine species are generated by two different pathways: choline addition to phosphatidic acid through the Kennedy pathway and trimethylation of phosphatidylethanolamine through phosphatidylethanolamine N‐methyl transferase (PEMT). Approach and Results Here, we report that a PEMT–LRH‐1 pathway specifically couples methyl metabolism and mitochondrial activities in hepatocytes. We show that the loss of Lrh‐1 reduces mitochondrial number, basal respiration, beta‐oxidation, and adenosine triphosphate production in hepatocytes and decreases expression of mitochondrial biogenesis and beta‐oxidation genes. In contrast, activation of LRH‐1 by its phosphatidylcholine agonists exerts opposite effects. While disruption of the Kennedy pathway does not affect the LRH‐1‐mediated regulation of mitochondrial activities, genetic or pharmaceutical inhibition of the PEMT pathway recapitulates the effects of Lrh‐1 knockdown on mitochondria. Furthermore, we show that S‐adenosyl methionine, a cofactor required for PEMT, is sufficient to induce Lrh‐1 transactivation and consequently mitochondrial biogenesis. Conclusions A PEMT–LRH‐1 axis regulates mitochondrial biogenesis and beta‐oxidation in hepatocytes.

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confidence: 93%

Methyl‐Sensing Nuclear Receptor Liver Receptor Homolog‐1 Regulates Mitochondrial Function in Mouse Hepatocytes

et al. 2019

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“…Fsp27β/CIDEC null mutation protects mice from obesity, hepatosteatosis, and insulin resistance (IR) induced by a high-fat diet (HFD) in association with changes in energy expenditure [9]. F Furthermore, Fsp27β/CIDEC is reported to be a steatosis-and steatohepatitis-specific gene, which marks the pathogenesis of NAFLD [10,11]. Thus, Fsp27β/CIDEC is a key player in the development and progression of NAFLD.…”

Section: Introductionmentioning

confidence: 99%

Resveratrol Ameliorates Lipid Droplet Accumulation in Liver Through a SIRT1/ ATF6-Dependent Mechanism

Zhou

et al. 2018

Cell Physiol Biochem

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Background/Aims: Lipid droplets (LDs) are dynamic organelles that store neutral lipids during times of energy excess, and an increased accumulation of LDs in the liver is closely linked to hepatic steatosis. Our previous studies suggested that resveratrol (RSV) supplement could improve hepatic steatosis, but the underlying mechanism, particularly which related to LD accumulation, has not yet been elucidated. Methods: A high-fat diet (HFD) and palmitic acid were used to induce hepatic steatosis in mouse liver and hepatocytes, respectively. The effects of RSV on LD accumulation were analyzed in vivo and in vitro. The effects of RSV on the expression levels of LD-associated genes (ATF6, Fsp27β/CIDEC, CREBH, and PLIN1) were measured by qRT-PCR and western blot assays, followed by KD or overexpression of SIRT1 and ATF6 with small interfering RNAs or overexpressed plasmids, respectively. The dual luciferase reporter assay, chromatin immunoprecipitation assay, coimmunoprecipitation, and proximity ligation assay were utilized to clarify the mechanism of transcriptional regulation and possible interaction between SIRT1 and ATF6. Results: There was a significant increase in the accumulation of LDs in liver and hepatocytes during the process of HFD-induced steatosis, respectively, which was significantly inhibited by RSV supplementation. RSV notably activated SIRT1 expression and decreased the expression levels of ATF6, Fsp27β/CIDEC, CREBH, and PLIN1, which are associated with LD accumulation. Interestingly, the inhibitory effects of RSV on LD accumulation and the associated expression of genes in hepatocytes were abrogated or strengthened with SIRT1 silencing or overexpression, respectively. On the contrary, the benefits of RSV in hepatocytes were eliminated or aggravated when transfected with the overexpressed ATF6 or ATF6 siRNA, respectively. Furthermore, we found that RSV stimulated SIRT1 expression significantly, which was followed by increased deacetylation and inactivation of ATF6, resulting in a positive feedback loop for SIRT1 transcription associated with ATF6 binding to the SIRT1 promoter region. Conclusion: Taken together, these findings indicate that RSV supplementation improves hepatic steatosis by ameliorating the accumulation of LDs, and this might be partially mediated by a SIRT1/ATF6-dependent mechanism.

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“…Ning et al, ; Yin et al, ). Moreover, several hepatic TFs were found repressed in NAFLD (Sahini & Borlak, ); and multiple genes encoding hepatic TFs have been associated with genetic risk of NAFLD, including TCF7L2 , SREBPF1/2 , CLOCK , STAT3 , and KLF6 (Wood, Miller, & Dillon, ).…”

Section: Nafld‐associated Remodeling Of Liver Gene Regulatory Landscapesmentioning

confidence: 99%

Liver gene regulatory networks: Contributing factors to nonalcoholic fatty liver disease

Cebola

2020

WIREs Mechanisms of Disease

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Metabolic diseases such as nonalcoholic fatty liver disease (NAFLD) result from complex interactions between intrinsic and extrinsic factors, including genetics and exposure to obesogenic environments. These risk factors converge in aberrant gene expression patterns in the liver, which are underlined by altered cis‐regulatory networks. In homeostasis and in disease states, liver cis‐regulatory networks are established by coordinated action of liver‐enriched transcription factors (TFs), which define enhancer landscapes, activating broad gene programs with spatiotemporal resolution. Recent advances in DNA sequencing have dramatically expanded our ability to map active transcripts, enhancers and TF cistromes, and to define the 3D chromatin topology that contains these elements. Deployment of these technologies has allowed investigation of the molecular processes that regulate liver development and metabolic homeostasis. Moreover, genomic studies of NAFLD patients and NAFLD models have demonstrated that the liver undergoes pervasive regulatory rewiring in NAFLD, which is reflected by aberrant gene expression profiles. We have therefore achieved an unprecedented level of detail in the understanding of liver cis‐regulatory networks, particularly in physiological conditions. Future studies should aim to map active regulatory elements with added levels of resolution, addressing how the chromatin landscapes of different cell lineages contribute to and are altered in NAFLD and NAFLD‐associated metabolic states. Such efforts would provide additional clues into the molecular factors that trigger this disease. This article is categorized under: Biological Mechanisms > Metabolism Biological Mechanisms > Regulatory Biology Laboratory Methods and Technologies > Genetic/Genomic Methods

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Genomics of human fatty liver disease reveal mechanistically linked lipid droplet–associated gene regulations in bland steatosis and nonalcoholic steatohepatitis

Cited by 32 publications

References 156 publications

Methyl‐Sensing Nuclear Receptor Liver Receptor Homolog‐1 Regulates Mitochondrial Function in Mouse Hepatocytes

Methyl‐Sensing Nuclear Receptor Liver Receptor Homolog‐1 Regulates Mitochondrial Function in Mouse Hepatocytes

Resveratrol Ameliorates Lipid Droplet Accumulation in Liver Through a SIRT1/ ATF6-Dependent Mechanism

Liver gene regulatory networks: Contributing factors to nonalcoholic fatty liver disease

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