Target of Suv420h1/2 in Hepatocytes

Summary

Nonalcoholic fatty liver disease (NAFLD) is globally the leading cause of liver disease and frequently progresses to cirrhosis and liver cancer. The identification of effective drugs is the main unmet clinical need. Changes in liver histones methylation accompanies the development and progression of NAFLD. Our preliminary data demonstrate that inactivation of the methyltransferases SUV420H1/2 in hepatocytes protects mice against NAFLD. In this project we propose to examine the relevance of these findings by evaluating the impact of genetic deletion of hepatic SUV420H1/2 in mice fed a steatogenic diet. To further evaluate the potential for clinical translation of these results, we will next 1) evaluate the expression of SUV420H1/2 in human liver transcriptomic data and 2) analyze the impact of genetic variations on disease outcomes in population-based cohorts; 3) test an innovative therapeutic approach based on hepatocyte-targeted antisense oligonucleotides downregulating SUV420H1/2 in human liver organoids/assembloids.

Eligibility

Inclusion Criteria:

We will analyse data and samples from subjects with the following criteria:

* Subjects aged\>18;
* Subjects who have already given their consent to genetic analysis and whose samples and data have already been collected as part of the SERENA, REASON and MAFALDA studies;
* Subjects who have given their consent to participate in this study.

In particular, subjects with the following characteristics were included respectively:

* in the SERENA study:

  1. Diagnosis of NAFLD
  2. Age between 45 and 75 years old
  3. Any of the following criteria:

     1. F3-F4 fibrosis, determined histologically, or by non-invasive techniques, or evidence of cirrhosis deriving from biochemical tests or imaging methods;
     2. Family history of related first-degree primary liver cancer, or carrier status of rare mutations associated with the development of HCC (such as mutations in APOB and TERT)
     3. Male patient with type 2 diabetes or obesity carrying at least three genetic variants in PNPLA3, TM6SF2, MBOAT7.
* in the REASON study:

Patients aged\>18, who have given their consent to participate in the study, who underwent the fol- lowing procedures:

* liver biopsy for suspected non-alcoholic steatohepatitis (NASH) at the time of diagnosis;
* liver resection for hepatocarcinoma, other liver lesions (including secondaries from other neo- plasms and benign focal lesions, which will allow obtaining healthy starting liver tissue), biopsies of whole liver explants obtained at the time of liver transplantation AND cholecystectomies.
* In the MAFALDA study:

Patients undergoing bariatric surgery for grade 3 obesity (BMI ≥40 Kg/m2) or grade 2 obesity plus:

* metabolic comorbidities (uncontrolled hypertension, diabetes, dyslipidemia);
* lack of contraindication to surgery (e.g. advanced liver disease with portal hypertension);
* willingness to sign an informed consent.

Exclusion Criteria:

* Individuals not reporting one of the inclusion criteria listed above or reporting at-risk alcohol intake (\>30/20 g/day in M/F), viral and autoimmune hepatitis or other causes of liver disease will be ex- cluded.

Conditions2

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