Pub Date : 2024-11-15DOI: 10.1016/j.jhep.2024.10.048
Yang Wang, Sen Hong, Hannah Hudson, Nora Kory, Lisa N. Kinch, Julia Kozlitina, Jonathan C. Cohen, Helen H. Hobbs
Background & Aims
PNPLA3(148M) (patatin-like phospholipase domain-containing protein 3) is the most impactful genetic risk factor for steatotic liver disease (SLD). A key unresolved issue is whether PNPLA3(148M) confers a loss- or gain-of-function. Here we test the hypothesis that PNPLA3 causes steatosis by sequestering ABHD5 (α/β hydrolase domain containing protein 5), the cofactor of ATGL (adipose TG lipase), thus limiting mobilization of hepatic triglyceride (TG).
Methods
We quantified and compared the physical interactions between ABHD5 and PNPLA3/ATGL in cultured hepatocytes using NanoBiT complementation assays and immunocytochemistry. Recombinant proteins purified from human cells were used to compare TG hydrolytic activities of PNPLA3 and ATGL in the presence or absence of ABHD5. Adenoviruses and adeno-associated viruses were used to express PNPLA3 in liver-specific Atgl-/- mice and to express ABHD5 in livers of Pnpla3M/M mice, respectively.
Results
ABHD5 interacted preferentially with PNPLA3 relative to ATGL in cultured hepatocytes. No differences were seen in the strength of the interactions between ABHD5 with PNPLA3(WT) and PNPLA3(148M). In contrast to prior findings, we found that PNPLA3, like ATGL, is activated by ABHD5 in in vitro assays using purified proteins. PNPLA3(148M)-associated inhibition of TG hydrolysis required that ATGL be expressed and that PNPLA3 be located on LDs. Finally, overexpression of ABHD5 reversed the hepatic steatosis in Pnpla3M/M mice.
Conclusions
These findings support the premise that PNPLA3(148M) is a gain-of-function mutation that promotes hepatic steatosis by accumulating on LDs and inhibiting ATGL-mediated lipolysis in an ABHD5-dependent manner. Our results predict that reducing, rather that increasing, PNPLA3 expression will be the best strategy to treat PNPLA3(148M)-associated SLD.
Impact and implications
Steatotic liver disease (SLD) is a common complex disorder associated with both environmental and genetic risk factors. PNPLA3(148M) is the most impactful genetic risk factor for SLD and yet its pathogenic mechanism remains controversial. Here we provide evidence that PNPLA3(148M) promotes triglyceride (TG) accumulation by sequestering ABHD5, thus limiting its availability to activate ATGL. Although the substitution of methionine for isoleucine reduces the TG hydrolase activity of PNPLA3, the loss of enzymatic function is not directly related to the steatotic effect of the variant. It is the resulting accumulation of PNPLA3 on LDs that confers a gain-of-function by interfering with ATGL-mediated TG hydrolysis. These findings have implications for the design of potential PNPLA3(148M)-based therapies. Reducing, rather than increasing, PNPLA3 levels is predicted to reverse steatosis in susceptible individuals.
{"title":"PNPLA3(148M) is a gain-of-function mutation that promotes hepatic steatosis by inhibiting ATGL-mediated triglyceride hydrolysis","authors":"Yang Wang, Sen Hong, Hannah Hudson, Nora Kory, Lisa N. Kinch, Julia Kozlitina, Jonathan C. Cohen, Helen H. Hobbs","doi":"10.1016/j.jhep.2024.10.048","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.10.048","url":null,"abstract":"<h3>Background & Aims</h3>PNPLA3(148M) (patatin-like phospholipase domain-containing protein 3) is the most impactful genetic risk factor for steatotic liver disease (SLD). A key unresolved issue is whether PNPLA3(148M) confers a loss- or gain-of-function. Here we test the hypothesis that PNPLA3 causes steatosis by sequestering ABHD5 (α/β hydrolase domain containing protein 5), the cofactor of ATGL (adipose TG lipase), thus limiting mobilization of hepatic triglyceride (TG).<h3>Methods</h3>We quantified and compared the physical interactions between ABHD5 and PNPLA3/ATGL in cultured hepatocytes using NanoBiT complementation assays and immunocytochemistry. Recombinant proteins purified from human cells were used to compare TG hydrolytic activities of PNPLA3 and ATGL in the presence or absence of ABHD5. Adenoviruses and adeno-associated viruses were used to express PNPLA3 in liver-specific <em>Atgl</em><sup><em>-/-</em></sup> mice and to express ABHD5 in livers of <em>Pnpla3</em><sup><em>M/M</em></sup> mice, respectively.<h3>Results</h3>ABHD5 interacted preferentially with PNPLA3 relative to ATGL in cultured hepatocytes. No differences were seen in the strength of the interactions between ABHD5 with PNPLA3(WT) and PNPLA3(148M). In contrast to prior findings, we found that PNPLA3, like ATGL, is activated by ABHD5 in <em>in vitro</em> assays using purified proteins. PNPLA3(148M)-associated inhibition of TG hydrolysis required that ATGL be expressed and that PNPLA3 be located on LDs. Finally, overexpression of ABHD5 reversed the hepatic steatosis in <em>Pnpla3</em><sup><em>M/M</em></sup> mice.<h3>Conclusions</h3>These findings support the premise that PNPLA3(148M) is a gain-of-function mutation that promotes hepatic steatosis by accumulating on LDs and inhibiting ATGL-mediated lipolysis in an ABHD5-dependent manner. Our results predict that reducing, rather that increasing, PNPLA3 expression will be the best strategy to treat PNPLA3(148M)-associated SLD.<h3>Impact and implications</h3>Steatotic liver disease (SLD) is a common complex disorder associated with both environmental and genetic risk factors. PNPLA3(148M) is the most impactful genetic risk factor for SLD and yet its pathogenic mechanism remains controversial. Here we provide evidence that PNPLA3(148M) promotes triglyceride (TG) accumulation by sequestering ABHD5, thus limiting its availability to activate ATGL. Although the substitution of methionine for isoleucine reduces the TG hydrolase activity of PNPLA3, the loss of enzymatic function is not directly related to the steatotic effect of the variant. It is the resulting accumulation of PNPLA3 on LDs that confers a gain-of-function by interfering with ATGL-mediated TG hydrolysis. These findings have implications for the design of potential PNPLA3(148M)-based therapies. Reducing, rather than increasing, PNPLA3 levels is predicted to reverse steatosis in susceptible individuals.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"246 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-15DOI: 10.1016/S0168-8278(24)02609-6
{"title":"LIVERAIM is an IHI funded project that is working to improve early detection of chronic liver disease through the development of a new biomarker-based personalized risk calculator","authors":"","doi":"10.1016/S0168-8278(24)02609-6","DOIUrl":"10.1016/S0168-8278(24)02609-6","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"81 6","pages":"Page v"},"PeriodicalIF":26.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-15DOI: 10.1016/S0168-8278(24)02608-4
{"title":"Register now for the EASL Liver Cancer Summit 2025, 20-22 February in Paris","authors":"","doi":"10.1016/S0168-8278(24)02608-4","DOIUrl":"10.1016/S0168-8278(24)02608-4","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"81 6","pages":"Page iv"},"PeriodicalIF":26.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-15DOI: 10.1016/S0168-8278(24)02607-2
{"title":"Register now for the EASL SLD Summit 2025, 23-25 January in Estoril","authors":"","doi":"10.1016/S0168-8278(24)02607-2","DOIUrl":"10.1016/S0168-8278(24)02607-2","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"81 6","pages":"Page iii"},"PeriodicalIF":26.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-15DOI: 10.1016/j.jhep.2024.07.001
Sara Battistella , Francesco Piazza , Marco Pizzi , Silvia Zanella , Francesco Paolo Russo
{"title":"From shadows to light: An unusual case of a hepatic mass","authors":"Sara Battistella , Francesco Piazza , Marco Pizzi , Silvia Zanella , Francesco Paolo Russo","doi":"10.1016/j.jhep.2024.07.001","DOIUrl":"10.1016/j.jhep.2024.07.001","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"81 6","pages":"Pages e261-e263"},"PeriodicalIF":26.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-15DOI: 10.1016/S0168-8278(24)02606-0
{"title":"Submit your abstract for the EASL Congress 2025 by 3 December","authors":"","doi":"10.1016/S0168-8278(24)02606-0","DOIUrl":"10.1016/S0168-8278(24)02606-0","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"81 6","pages":"Page ii"},"PeriodicalIF":26.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Intrahepatic cholestasis of pregnancy (ICP) is the most common and high-risk liver disorder during pregnancy, with varying prevalence across populations. Our understanding of the mechanisms underlying ICP and its population difference remains limited. This study delves into the genetic etiology of ICP in East Asians, drawing comparisons with Europeans to comprehend ICP etiology in the context of genetic background and evolution.
Methods
We conducted the hitherto largest-scale genome-wide association studies (GWAS) on fasting total serum bile acids (TBA) and ICP in 98,269 Chinese pregnancies. The findings were replicated in three cohorts and compared with European populations. Additionally, phenome-wide association and spatio-temporal evolution analyses were employed to investigate the function and evolutionary patterns of ICP-associated loci.
Results
We identified eight loci for fasting TBA and four for ICP, including ten novel loci. Notably, we discovered an East-Asian-specific locus within a 0.4Mbp region at 14q24.1, which increases fasting TBA by 6.12 μmol/L and ICP risk by 16.56-fold per risk allele (95% CI: 16.43 to 16.69, P = 7.06×10-381). Phenome-wide association and spatial-temporal evolution analyses revealed that this 14q24.1 ICP risk locus confers resistance to hepatitis B and has become prevalent in East and Southeast Asia within the last 3,000 years.
Conclusions
We uncovered a distinct genetic etiology of ICP in East Asians, likely linked to a historic HBV epidemic in East and Southeast Asia within the last 3,000 years. These findings enhance our understanding of ICP pathophysiology and offer potential for more precise detection, assessment, and treatment of the disorder.
Impact and implications
This study provides novel insights into the genetic basis of intrahepatic cholestasis of pregnancy (ICP) in East Asian populations, where little was previously known. The identification of the East-Asian-specific 14q24.1 locus, associated with both fasting TBA and ICP, and its connection to a historical hepatitis B epidemic emphasize the importance of incorporating population-specific history into disease research. These findings are crucial for researchers studying pregnancy-related liver disorders and clinicians providing care to pregnant women, enabling more accurate screening, risk assessment, and targeted interventions for ICP.
{"title":"Genetic study of intrahepatic cholestasis of pregnancy in Chinese women unveils East Asian etiology linked to historic HBV epidemic","authors":"Yanhong Liu, Yuandan Wei, Xiaohang Chen, Shujia Huang, Yuqin Gu, Zijing Yang, Xinxin Guo, Hao Zheng, Hanxiao Feng, Mingxi Huang, Shangliang Chen, Tiantian Xiao, Liang Hu, Quanfu Zhang, Yang Zhang, Guo-Bo Chen, Xiu Qiu, Fengxiang Wei, Jianxin Zhen, Siyang Liu","doi":"10.1016/j.jhep.2024.11.008","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.11.008","url":null,"abstract":"<h3>Background & Aims</h3>Intrahepatic cholestasis of pregnancy (ICP) is the most common and high-risk liver disorder during pregnancy, with varying prevalence across populations. Our understanding of the mechanisms underlying ICP and its population difference remains limited. This study delves into the genetic etiology of ICP in East Asians, drawing comparisons with Europeans to comprehend ICP etiology in the context of genetic background and evolution.<h3>Methods</h3>We conducted the hitherto largest-scale genome-wide association studies (GWAS) on fasting total serum bile acids (TBA) and ICP in 98,269 Chinese pregnancies. The findings were replicated in three cohorts and compared with European populations. Additionally, phenome-wide association and spatio-temporal evolution analyses were employed to investigate the function and evolutionary patterns of ICP-associated loci.<h3>Results</h3>We identified eight loci for fasting TBA and four for ICP, including ten novel loci. Notably, we discovered an East-Asian-specific locus within a 0.4Mbp region at 14q24.1, which increases fasting TBA by 6.12 μmol/L and ICP risk by 16.56-fold per risk allele (95% <em>CI</em>: 16.43 to 16.69, <em>P</em> = 7.06×10<sup>-381</sup>). Phenome-wide association and spatial-temporal evolution analyses revealed that this 14q24.1 ICP risk locus confers resistance to hepatitis B and has become prevalent in East and Southeast Asia within the last 3,000 years.<h3>Conclusions</h3>We uncovered a distinct genetic etiology of ICP in East Asians, likely linked to a historic HBV epidemic in East and Southeast Asia within the last 3,000 years. These findings enhance our understanding of ICP pathophysiology and offer potential for more precise detection, assessment, and treatment of the disorder.<h3>Impact and implications</h3>This study provides novel insights into the genetic basis of intrahepatic cholestasis of pregnancy (ICP) in East Asian populations, where little was previously known. The identification of the East-Asian-specific 14q24.1 locus, associated with both fasting TBA and ICP, and its connection to a historical hepatitis B epidemic emphasize the importance of incorporating population-specific history into disease research. These findings are crucial for researchers studying pregnancy-related liver disorders and clinicians providing care to pregnant women, enabling more accurate screening, risk assessment, and targeted interventions for ICP.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"36 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Non-responder on thyroid hormone receptor-β agonist? Bacteroides thetaiotaomicron to the rescue!","authors":"Abraham S. Meijnikman, Eveline Bruinstroop","doi":"10.1016/j.jhep.2024.11.009","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.11.009","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Acknowledgements</h2>A.M. is supported by a personal ZONMW-VENI grant 2023 (09150162310148)</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"35 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.jhep.2024.10.046
Frank J. Gonzalez, Yangliu Xia
Section snippets
Financial support
Funded by the National Cancer Institute Intramural Research Program.
Declaration of Competing Interest
The authors declare no conflicts of interest that pertain to this work.Please refer to the accompanying ICMJE disclosure forms for further details.Adipose triglyceride lipase (ATGL), encoded by the PNPLA2 gene in humans, hydrolyzes triacylglycerols to diacylglycerols. PNPLA2 is regulated by insulin, and under conditions of insulin resistance, increased adipocyte ATGL leads to excess production of free fatty acids that are transported to the liver resulting in metabolic dysfunction-associated
{"title":"Adipose triglyceride lipase as a target for treatment of metabolic dysfunction-associated steatohepatitis: the role of hepatic and intestinal PPARα","authors":"Frank J. Gonzalez, Yangliu Xia","doi":"10.1016/j.jhep.2024.10.046","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.10.046","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Financial support</h2>Funded by the National Cancer Institute Intramural Research Program.</section></section><section><section><h2>Declaration of Competing Interest</h2>The authors declare no conflicts of interest that pertain to this work.Please refer to the accompanying ICMJE disclosure forms for further details.Adipose triglyceride lipase (ATGL), encoded by the <em>PNPLA2</em> gene in humans, hydrolyzes triacylglycerols to diacylglycerols. <em>PNPLA2</em> is regulated by insulin, and under conditions of insulin resistance, increased adipocyte ATGL leads to excess production of free fatty acids that are transported to the liver resulting in metabolic dysfunction-associated</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"37 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Activating hepatobiliary water channels for gallstone prevention in complicated gallstone disease","authors":"Jan G. Hengstler, Nachiket Vartak","doi":"10.1016/j.jhep.2024.11.006","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.11.006","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Conflict of interest statement</h2>The authors declare no conflict of interest.</section></section><section><section><h2>Uncited reference</h2>[17]; [18]; [19]; [17]; [18]; [19].</section></section><section><section><h2>Authors' contributions</h2>JGH and NV developed the ideas presented and wrote the manuscript.</section></section><section><section><h2>Financial support</h2>No particulars to report</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"35 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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