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, Marica; Paolini, Erika; Erconi, Veronica; Carli, Fabrizia; Fortunato, Francesco; Ronchi, Dario; Piciotti, Roberto; Sabatini, Silvia; Macchi, Chiara; Alisi, Anna; Miele, Luca; Soardo, Giorgio; Comi, Giacomo Pietro; Valenti, Luca; Ruscica, Massimiliano; Gastaldelli, Amalia; Dongiovanni, Paola

doi:10.1016/j.jcmgh.2021.11.007

Cited by 58 publications

(59 citation statements)

References 52 publications

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“…In the future, comprehensive analysis including anti-HBc, hepatitis B surface antibody, and HBV DNA status is required to clarify the role of OBI in these special populations. Finally, the gene polymorphisms including TM6SF2/PNPLA3/MBOAT7 which are highly related to the abnormal metabolic disease and fatty liver disease are not evaluated in our study ( 57 , 58 ). Futher studies are needed to investigated whether the proportion of SNPs in NBNC-HCC is getting higher.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Risks Are Increasing in Non-B Non-C Early-Stage Hepatocellular Carcinoma: A 10-Year Follow-Up Study

et al. 2022

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BackgroundNon-B, non-C hepatocellular carcinoma (NBNC-HCC) may be related to metabolic syndrome, and the incidence of this tumor type is increasing annually. The definition of metabolic-associated fatty liver disease (MAFLD) proposed in 2020 may help to more accuratelyassess the association between metabolic syndrome and NBNC-HCC. However, this new concept has not yet been applied in NBNC-HCC research. Therefore, this study aimed to compare the clinicopathological characteristics of patients with NBNC-HCC and CHB-HCC diagnosed between 2009-13 and 2014-18, focusing on metabolic risk factors and the new concept of MAFLD.MethodPatients with BCLC-0/A-HCC who received curative hepatectomy between January 2009 and December 2018 were retrospectively assessed; the associations between clinicopathological characteristics and clinical outcomes of NBNC-HCC and CHB-HCC were analyzed by multivariate analysis.ResultCompared to patients diagnosed in 2009-13, the frequency of metabolic disorders in NBNC-HCC was significantly higher in 2014-18 [DM (p=0.049), HTN (p=0.004), BMI (p=0.017) and MAFLD (p=0.003)]; there was no significant change in patients with CHB-HCC. Moreover, CHB-HCC was an independent risk factor for HCC recurrence (HR, 1.339; 95% CI, 1.010-1.775, p=0.043) and death (HR, 1.700; 95% CI, 1.017-2.842, p=0.043) compared to NBNC-HCC.ConclusionsTherisk of MAFLD, obesity, DM, and hypertension in patients with early-stage NBNC have significantly increased in recent years, thus metabolic syndrome should be monitored in this special population. Moreover, NBNC-HCC tend to had a better prognosis than CHB-HCC, probably due to their distinct clinicopathological features.

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Section: Discussionmentioning

confidence: 99%

Metabolic Risks Are Increasing in Non-B Non-C Early-Stage Hepatocellular Carcinoma: A 10-Year Follow-Up Study

et al. 2022

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“…The first procedure consists of editing the genetic defect by exploiting different technologies such as zinc finger nucleases, CRISPR-Cas9, and engineered, replicationincompetent viral vectors [88][89][90]. Among them, DNA transfer vectors derived from recombinant adeno-associated viruses (rAAV) have been successfully applied in the treatment of inherited disorders and, in recent years, they have been optimized to ensure the long-term expression of a specific protein, to ensure safety and tissue tropism, and to avoid immunogenicity [90][91][92].…”

Section: Gene Therapy Mrna-based Therapies and Apolipoprotein For Pro...mentioning

confidence: 99%

Cutting-Edge Therapies and Novel Strategies for Acute Intermittent Porphyria: Step-by-Step towards the Solution

et al. 2022

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Acute intermittent porphyria (AIP) is an autosomal dominant disease caused by the hepatic deficiency of porphobilinogen deaminase (PBGD) and the slowdown of heme biosynthesis. AIP symptomatology includes life-threatening, acute neurovisceral or neuropsychiatric attacks manifesting in response to precipitating factors. The latter promote the upregulation of 5-aminolevulinic acid synthase-1 (ALAS1), the first enzyme of heme biosynthesis, which promotes the overload of neurotoxic porphyrin precursors. Hemin or glucose infusions are the first-line therapies for the reduction of ALAS1 levels in patients with mild to severe AIP, while liver transplantation is the only curative treatment for refractory patients. Recently, the RNA-interference against ALAS1 was approved as a treatment for adult and adolescent patients with AIP. These emerging therapies aim to substitute dysfunctional PBGD with adeno-associated vectors for genome editing, human PBGD mRNA encapsulated in lipid nanoparticles, or PBGD protein linked to apolipoprotein A1. Finally, the impairment of glucose metabolism linked to insulin resistance, and mitochondrial aberrations during AIP pathophysiology provided new therapeutic targets. Therefore, the use of liver-targeted insulin and insulin-mimetics such as α-lipoic acid may be useful for overcoming metabolic dysfunction in these subjects. Herein, the present review aims to provide an overview of AIP pathophysiology and management, focusing on conventional and recent therapeutical approaches.

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“…Meanwhile, the I148M point mutation in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene represents one of the most significant predisposing factors to NAFLD development and advanced liver damage, indicating that there is also a genomic background in NAFLD pathogenesis [ 82 , 83 , 84 , 85 ]. In fact, it has been suggested that the accumulation of PNPLA3-148M on the surfaces of lipid droplets (LDs) inhibits triacylglycerol hydrolysis and leads to the impaired mobilization of triglycerides from LDs [ 86 , 87 , 88 ].…”

Section: Overview Of Non-alcoholic Fatty Liver Disease (Nafld)mentioning

confidence: 99%

Non-Alcoholic Fatty Liver Disease and Extrahepatic Cancers: A Wolf in Sheep’s Clothing?

et al. 2022

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Non-alcoholic fatty liver disease (NAFLD) is now considered the main driver and leading cause of chronic liver disease globally. The umbrella term NAFLD describes a range of liver conditions closely related to insulin resistance, metabolic syndrome, diabetes mellitus, obesity, and dyslipidemia. At the same time, several malignancies, including hepatocellular carcinoma and colorectal cancer, are considered to be common causes of death among patients with NAFLD. At first, our review herein aims to investigate the role of NAFLD in developing colorectal neoplasms and adenomatous polyps based on the current literature. We will also explore the connection and the missing links between NAFLD and extrahepatic cancers. Interestingly, any relationship between NAFLD and extrahepatic malignancies could be attributable to several shared metabolic risk factors. Overall, obesity, insulin resistance, metabolic syndrome, and related disorders may increase the risk of developing cancer. Therefore, early diagnosis of NAFLD is essential for preventing the progression of the disease and avoiding its severe complications. In addition, cancer screening and early detection in these patients may improve survival and reduce any delays in treatment.

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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 58 publications

References 52 publications

Metabolic Risks Are Increasing in Non-B Non-C Early-Stage Hepatocellular Carcinoma: A 10-Year Follow-Up Study

Metabolic Risks Are Increasing in Non-B Non-C Early-Stage Hepatocellular Carcinoma: A 10-Year Follow-Up Study

Cutting-Edge Therapies and Novel Strategies for Acute Intermittent Porphyria: Step-by-Step towards the Solution

Non-Alcoholic Fatty Liver Disease and Extrahepatic Cancers: A Wolf in Sheep’s Clothing?

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