TM6SF2/PNPLA3/MBOAT7 loss-of-function genetic variants impact on NAFLD development and progression both in patients and in in vitro models

Longo, Miriam; Meroni, M.; Erconi, Veronica; Alisi, Anna; Miele, Luca; Rametta, Raffaela; Valenti, L.; Dongiovanni, Paola

doi:10.1016/j.dld.2019.12.021

Cited by 5 publications

(6 citation statements)

References 41 publications

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“…Similar observations were made in Western populations for PNPLA3 rs738409[18,19]. Also, TM6SF2 rs58542926[20] and MBOAT7 rs641738[7,21,22] have indicated signi cant contributions to the NAFLD-HCC etiology.…”

supporting

confidence: 75%

Association and impact of SNPs in PNPLA3, TM6SF2 and MBOAT7 genes on prognosis factors of hepatocellular carcinoma with non-viral etiology

Samarasinghe

Hewage

Siriwardena

et al. 2022

Preprint

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Background: Hepatocellular carcinoma (HCC) is becoming a challenging global health concern with Asian and African countries carrying the highest burden of it. The rising prevalence of non-alcoholic steatohepatitis (NASH) associated HCC is linked with unhealthy dietary patterns and sedentary life styles. In addition, genetic predisposition may play a critical role in developing NASH-related HCC. Previous studies have identified that variants in patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2) and membrane bound O-acyltransferase domain containing 7 (MBOAT7) genes are significantly associated with non-alcoholic fatty liver disease (NAFLD) pathogenicity among different populations. But there are no published reports on their impact on Sri Lankan NASH-HCC patients. Methods: We conducted an exploratory study to evaluate the prevalence of five single nucleotide polymorphisms (SNPs) (PNPLA3 rs738409, PNPLA3rs2281135, PNPLA3 rs2294918, TM6SF2 rs58542926 and MBOAT7 rs641738) as genetic risk factors for NASH-HCC pathogenicity. We genotyped 48 NASH-HCC samples that were collected at a clinical setting and analyzed using statistical modelling to explore the impact of each SNP with tumor prognostic factors. Results: We observed high frequencies in four out of five polymorphisms, namely PNPLA3 rs738409 (0.79, 95%CI 0.650-0.895), PNPLA3 rs2281135 (0.77, 95%CI 0.627-0.880), PNPLA3 rs2294918 (0.9, 95%CI 0.773-0.965) and MBOAT7rs641738 (0.85, 95%CI 0.722-0.939) among Sri Lankan NASH-HCC patients. Our analyses further demonstrated significant associations of PNPLA3variants with a total tumor diameter of NASH-HCC patients while PNPLA3 rs2294918 and MBOAT7 rs641738 had significant associations with single-nodular HCC. Of the five SNPs, we observed a strong correlation between PNPLA3 rs738409 and PNPLA3 rs2294918 through pairwise linkage disequilibrium (LD) analysis. Conclusion: Observed high frequencies of risk alleles among genotyped SNPs warrants the possibility of genetic predisposition as a risk factor for NASH-related HCC in the Sri Lankan setting.

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supporting

confidence: 75%

Association and impact of SNPs in PNPLA3, TM6SF2 and MBOAT7 genes on prognosis factors of hepatocellular carcinoma with non-viral etiology

Samarasinghe

Hewage

Siriwardena

et al. 2022

Preprint

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“…We revealed that both TM6SF2 −/− and MBOAT7 −/−/ TM6SF2 −/− are characterized by an enrichment in the number of mitochondria with small and globular shape, loss of cistern architecture and ultrastructural electron density which may indicate mitochondrial failure and degeneration. Notably, the compound KO model runs into metabolic reprogramming towards anaerobic glycolysis, supporting that the co-absence of TM6SF2 and MBOAT7 deletions together with the presence of the PNPLA3 p.I148M mutation may synergically affect mitochondrial metabolism within the hepatocytes thus contributing to progressive liver damage and possibly triggers the switch towards HCC [248,249].…”

Section: Novel Insights Into the Modelling Of Nafld: From Genetic Studies To Cellular Modelsmentioning

confidence: 91%

Genetics Is of the Essence to Face NAFLD

et al. 2021

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Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. It is closely related to obesity, insulin resistance (IR) and dyslipidemia so much so it is considered the hepatic manifestation of the Metabolic Syndrome. The NAFLD spectrum extends from simple steatosis to nonalcoholic steatohepatitis (NASH), a clinical condition which may progress up to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). NAFLD is a complex disease whose pathogenesis is shaped by both environmental and genetic factors. In the last two decades, several heritable modifications in genes influencing hepatic lipid remodeling, and mitochondrial oxidative status have been emerged as predictors of progressive hepatic damage. Among them, the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, the Transmembrane 6 superfamily member 2 (TM6SF2) p.E167K and the rs641738 membrane bound-o-acyltransferase domain-containing 7 (MBOAT7) polymorphisms are considered the most robust modifiers of NAFLD. However, a forefront frontier in the study of NAFLD heritability is to postulate score-based strategy, building polygenic risk scores (PRS), which aggregate the most relevant genetic determinants of NAFLD and biochemical parameters, with the purpose to foresee patients with greater risk of severe NAFLD, guaranteeing the most highly predictive value, the best diagnostic accuracy and the more precise individualized therapy.

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“…The protein levels of the ER stress marker BiP and IRE1α were upregulated only in HepG2 cells stably overexpressing PNPLA3 M148M, a finding that points towards a transcriptional activation of PNPLA3 I148M by NF‐κB that leads to increased TNF‐α expression through the ER stress IRE1α/JNK/c‐Jun pathway in HepG2 cells treated long‐term with palmitic acid 128 . TM6SF2 deletion in HepG2 cells strongly affected ER and mitochondria ultrastructures, thus increasing ER/oxidative stress and increased the mRNA levels of ATF4, XBP1 , and GRP78 129 . MBOAT7 deletion in HepG2 cells led to increased GRP78 mRNA expression and a significant enlargement of the ER lumen, although its architecture was still preserved, suggesting that a mild unfolded protein response is associated with MBOAT7 deletion 129 .…”

Section: Genetic and Hormonal Effects On The Er Stress Pathways In Hu...mentioning

confidence: 98%

“…TM6SF2 deletion in HepG2 cells strongly affected ER and mitochondria ultrastructures, thus increasing ER/oxidative stress and increased the mRNA levels of ATF4, XBP1 , and GRP78 129 . MBOAT7 deletion in HepG2 cells led to increased GRP78 mRNA expression and a significant enlargement of the ER lumen, although its architecture was still preserved, suggesting that a mild unfolded protein response is associated with MBOAT7 deletion 129 . Of interest, double MBOAT7‐TM6SF2 knockout HepG2 cells showed an, even more, exacerbated breakage and enlargement of ER tubules, high local curvature of ER membranes, and increased mRNA levels of ATF4, ATF6, XBP1 and GRP78 129 …”

Section: Genetic and Hormonal Effects On The Er Stress Pathways In Hu...mentioning

confidence: 98%

Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD)

Flessa

Kyrou

Nasiri-Ansari

et al. 2022

J of Cellular Biochemistry

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Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation in the absence of excessive alcohol consumption and is strongly associated with obesity, type 2 diabetes (T2DM) and other metabolic syndrome features. NAFLD is becoming increasingly prevalent and currently constitutes the leading cause of hepatocellular carcinoma (HCC). Recently, the term metabolic (dysfunction) associated fatty liver disease (MAFLD) has been proposed reflecting more accurately the underlying pathogenesis and the cardiometabolic disorders associated to NAFLD/MAFLD. Given the vital metabolic functions of the liver to maintain the body homeostasis, an extended endoplasmic reticulum (ER) network is mandatory in hepatocytes to retain its capacity to adapt to the multiple extracellular and intracellular signals mediating metabolic changes. Dysfunction of hepatocyte ER homeostasis and disturbance of its interaction with mitochondria have been recognized to be involved in the NAFLD pathophysiology. Apart from hepatocytes, hepatic stellate cells, and Kupffer cells have been shown to play an important role in the occurrence of NAFLD and progression to nonalcoholic steatohepatitis (NASH) with possibly different roles in the different stages of the NAFLD spectrum. Furthermore, excess lipid accumulation in the liver causes lipotoxicity which interacts with ER stress and culminates in inflammation and hepatocellular damage, mechanisms crucially implicated in NASH pathogenesis. Finally, the circadian clock machinery regulates ER stress‐related pathways and vice versa, thus controlling the homeostasis of the liver metabolism and being implicated in the NAFLD progression. This review presents a comprehensive overview of the current knowledge supporting the impact of ER stress signaling on NAFLD, whilst summarizing potential therapeutic interventions targeting this process.

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TM6SF2/PNPLA3/MBOAT7 loss-of-function genetic variants impact on NAFLD development and progression both in patients and in in vitro models

Cited by 5 publications

References 41 publications

Association and impact of SNPs in PNPLA3, TM6SF2 and MBOAT7 genes on prognosis factors of hepatocellular carcinoma with non-viral etiology

Association and impact of SNPs in PNPLA3, TM6SF2 and MBOAT7 genes on prognosis factors of hepatocellular carcinoma with non-viral etiology

Genetics Is of the Essence to Face NAFLD

Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD)

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