Nature Metabolism PSD3 may become a new target for fatty liver treatment

Article | Fatty liver disease (FLD) is a disease caused by excessive accumulation of fat in liver cells due to various reasons.
It is a common liver pathological change and has become the main cause of liver damage worldwide [1 ]
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FLD ranges from simple steatosis to liver inflammation and fibrosis, with progression to advanced fibrosis leading to cirrhosis and hepatocellular carcinoma
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It has been reported that the worldwide prevalence of severe liver fibrosis associated with FLD is expected to double in the next 10 years and become the leading cause of liver failure and cancer, posing a major threat to public health [2]
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Despite the progress of drugs targeting metabolic abnormalities, no drugs are currently approved for the treatment of FLD [3]
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Therefore, there is an urgent need to develop new effective therapies and identify non-invasive biomarkers
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FLD has a familial aggregation phenomenon and has a certain genetic predisposition
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To date, single nucleotide sequence variants in PNPLA3, TM6SF2, GCKR, MBOAT7, HSD17B13, MARC1, APOE and GPAM have been shown to be associated with FLD [4-6]
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These genetic variants affect lipid metabolism within the liver by altering lipid secretion, lipid droplet remodeling, or increasing lipogenesis, and contribute to liver inflammation and fibrosis, increasing the risk of FLD onset and progression
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Despite recent advances in the field, common variants identified to date account for less than 6% of disease variants [7], so researchers are working to identify and uncover more unknown loci that affect liver fat content point
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On January 31, 2022, a research paper titled PSD3 downregulation confers protection against fatty liver disease was published online in the journal Nature Metabolism by Stefano Romeo's team from the University of Gothenburg, Sweden, in collaboration with Daniel Lindén's team from AstraZeneca, revealing that Pleckstrin and Relationship of Sec7 domain-containing 3 (PSD3) to FLD
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We identified a previously unknown locus in the PSD3 gene associated with liver fat content, rs71519934, that results in a leucine-to-threonine substitution (L186T) at position 186 of the PSD3 protein, reducing risk in high-risk individuals Susceptibility to FLD
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Mechanistically, down-regulation of PSD3 protects mice from FLD and prevents lipid accumulation in primary human hepatocytes and hepatoma cells
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This study opens up new ideas for the treatment of FLD
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To identify previously unknown genetic loci affecting hepatic fat content, the authors examined the association between candidate gene variants and hepatic fat content in the Dallas Heart Study (DHS) cohort (n = 2736) and in PSD3 A variant in the gene (rs71519934, L186T) was found to be associated with lower liver fat content (P=0.
049)
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The DHS is primarily composed of European Americans, African Americans, and Hispanics
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Post-racial analysis found that European Americans with the PSD3 rs71519934 genotype had lower circulating total cholesterol levels
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These data suggest that PSD3 rs71519934 is associated with FLD
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The authors then performed validation in different cohorts including (1) a liver biopsy cohort (Liver Biopsy Cohort, LBC; n=1951) - non-alcoholic fatty liver disease from northern and southern Europe , NAFLD) high-risk population; (2) participants from the UK Biobank cohort for which liver fat data were available (n = 10,970); (3) obese high-risk liver disease population with liver biopsy from Central Europe (n = 674) )
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All data show that PSD3 sequence variation reduces human susceptibility to FLD.
Therefore, the author's follow-up work will focus on exploring the molecular mechanism by which PSD3 affects FLD
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The PSD3 protein has 18 annotated isoforms, and by examining the transcriptomes of 77 liver biopsies from LBC, the authors found that isoform-a (marked as 001 ENST00000327040 in Ensembl) was expressed at the highest level in the liver
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It is worth noting that the level of PSD3 mRNA in the liver of patients with FLD was significantly higher than that of patients without FLD, while there was no significant difference in the level of N-acetyltransferase 2 (NAT2) mRNA; further analysis found that both PSD3 mRNA and NAT2 mRNA were in different PSD3 genes.
There were no significant differences in the expression levels among individuals
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The authors first investigated the association between the rs71519934 minor allele (186T was the minor allele in Europeans as shown by exome sequencing of samples from the UK Biobank) and low liver fat in primary human hepatocytes homozygous for 186L or 186T relationship between the contents
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Neutral lipid fat content was reduced in 186T human primary hepatocytes cultured in 2D compared to 186L human primary hepatocytes
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The authors cultured cells with different concentrations (0, 10 and 25 mM) of oleic acid (OA), and detected PSD3 protein levels in two genotypes of hepatocytes, and found that PSD3 expression levels increased with increasing OA concentrations high
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However, PSD3 protein expression was lower in 186T cells for different concentrations of OA
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By analyzing differentially expressed genes involved in lipid homeostasis by RNA-seq, the authors found that the expression of genes involved in triglyceride synthesis and secretion and cholesterol biosynthesis was significantly reduced
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Therefore, the authors speculate that PSD3 186T prevents intracellular lipid accumulation
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Since PSD3 expression is elevated in the liver of FLD patients, the authors wondered whether downregulation of PSD3 would reduce intracellular fat content
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As expected, down-regulation of PSD3 decreased neutral lipid content in hepatocytes carrying both 186L and 186T alleles under 2D culture conditions; however, PSD3 down-regulation only decreased when cultured in 3D spheroid models Intracellular lipid levels in primary hepatocytes carrying the 186L allele
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The authors then explored the molecular mechanisms underlying the genetic association in immortalized hepatocytes homozygous for 180T in rats (McArdle, McA-RH7777)
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The results showed that down-regulation of Psd3 could significantly reduce the intracellular neutral lipid content, triglyceride production, and mRNA expression levels of related genes involved in triglyceride synthesis
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The secretion of LDL was also lower in Psd3-knockdown cells compared with controls, while there was no difference in intracellular lipid utilization
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Meanwhile, the authors measured intracellular lipid accumulation and triglyceride synthesis in human hepatoma cells (Huh7 cells) homozygous for the PSD3 186L allele, and obtained exactly the same results as in McA-RH7777 cells, indicating that endogenous Downregulation of Psd3 186T or PSD3186L resulted in decreased intracellular lipid levels
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PSD3 is a guanine nucleotide exchange factor for activating ADP-ribosylation factor 6 (ARF6), and down-regulation of PSD3 will result in reduced levels of activated ARF6
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Finally, the authors explored the relationship between PSD3 downregulation and FLD in mice
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C57BL/6 mice were subjected to NASH (non-alcoholic steatohepatitis)-induced feeding for 50 weeks, and during the last 16 weeks, the mice were divided into Psd3 ASOs (antisense oligonucleotides, which can Effective knockdown of endogenous Psd3) treatment group and control ASO group
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The data showed that Psd3 ASO treatment reduced liver Psd3 mRNA expression levels by 98%, which in turn reduced liver weight, liver total triglyceride content, and plasma alanine transaminase (ALT) levels (Psd3 ASOs did not affect mouse body weight)
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In addition, Psd3 ASO decreased liver free total cholesterol, liver cholesterol esters, plasma aspartate transaminase (AST), total cholesterol, and LDL cholesterol levels, but did not alter plasma triglycerides or high-density lipoprotein (HDL) levels Cholesterol levels
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To gain insight into the mechanism by which Psd3 downregulation leads to decreased hepatic fat content, the authors examined the expression levels of genes involved in triglyceride synthesis
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Consistent with the in vitro results, downregulation of Psd3 decreased the expression of genes involved in fat synthesis (Fasn, Acc1, Scd1) and also decreased the expression level of monocyte chemoattractant protein 1 (Ccl2) in mice fed a NASH-induced diet
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The authors confirmed the above in vivo data again in another mouse model
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Collectively, this study identifies a novel liver fat content-related locus, rs71519934, in PSD3, which is involved in susceptibility to fatty liver in high-risk individuals; and in mouse, human primary hepatocytes The molecular mechanism behind the genetic association was explored in human and rodent hepatoma cells: PSD3/Psd3 downregulation protects mice from fatty liver and prevents lipid accumulation in human primary hepatocytes and hepatoma cells
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The authors believe that a more in-depth mechanistic analysis is needed to evaluate the potential of PSD3 in the treatment of FLD
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Original link: https://doi.
org/10.
1038/s42255-021-00518-0 Publisher: Eleven References 1.
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Instructions for reprinting【Original article】BioArt original article, welcome to forward and share personally, reprinting is prohibited without permission, and the copyright of all works published is owned by BioArtLeveraging human genetics to identify potential new treatments for fatty liver disease.
Cell Metab.
31, 35-45 (2020).
Instructions for reprinting【Original article】BioArt original article, welcome to repost and share, and reprint without permission is prohibited.
The copyright of the work is owned by BioArtLeveraging human genetics to identify potential new treatments for fatty liver disease.
Cell Metab.
31, 35-45 (2020).
Instructions for reprinting【Original article】BioArt original article, welcome to repost and share, and reprint without permission is prohibited.
The copyright of the work is owned by BioArt
.

BioArt reserves all legal rights and violators will be held accountable
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