International Journal of Molecular Sciences

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Dear Colleagues,

Fatty liver disease (FLD), also known as hepatic steatosis, is a term encompassing a spectrum of diseases that are characterized by lipid accumulation in the liver. FLD is histologically defined by an abnormal deposition of fat within more than 5% of hepatocytes. Even though it is a benign condition, it can progress to fibrosis and lead to end-stage liver disease.

Currently, FLD is considered a major cause of chronic liver diseases worldwide. It has been associated with different conditions—most frequently, alcohol abuse, chronic hepatitis C virus infection, and obesity. Indeed, obesity may cause FLD due to metabolic abnormalities such as visceral adiposity and insulin resistance, and this condition has recently been described by the umbrella term “metabolically associated FLD (MAFLD)”.

Besides these major causes of FLD in the adult population, in children, there is also a large group of genetic and metabolic disorders that can clinically present with FLD and/or high transaminase levels, and mimic or coexist with a diagnosis of paediatric MAFLD.

FLD, due to its multiple aetiologies, has different molecular and cellular mechanisms of development and progression.

This Special Issue aims to discuss the current knowledge on the pathophysiology of FLD and its progression in different forms of chronic liver diseases, including alcoholic fatty liver disease (ALD), MAFLD (NAFLD), and paediatric inherited metabolic disorders. Experimental studies, review articles, and clinical studies are welcome for consideration.

Prof. Gianluca Svegliati-Baroni
Dr. Anna Alisi
Guest Editors

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Keywords

MAFLD
ALD
NAFLD
Metabolic disorders
Fibrosis
Hepatocellular carcinoma
Genetics
Epigenetics
Omics

Published Papers (2 papers)

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Research

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18 pages, 1335 KiB

Open AccessArticle

The Propensity of the Human Liver to Form Large Lipid Droplets Is Associated with PNPLA3 Polymorphism, Reduced INSIG1 and NPC1L1 Expression and Increased Fibrogenetic Capacity

by Flaminia Ferri, Simone Carotti, Guido Carpino, Monica Mischitelli, Alfredo Cantafora, Antonio Molinaro, Maria Eva Argenziano, Simona Parisse, Alessandro Corsi, Mara Riminucci, Quirino Lai, Gianluca Mennini, Gustavo Spadetta, Francesco Pugliese, Massimo Rossi, Sergio Morini, Eugenio Gaudio and Stefano Ginanni Corradini

Int. J. Mol. Sci. 2021, 22(11), 6100; https://doi.org/10.3390/ijms22116100 - 05 Jun 2021

Cited by 4 | Viewed by 3024

Abstract

In nonalcoholic steatohepatitis animal models, an increased lipid droplet size in hepatocytes is associated with fibrogenesis. Hepatocytes with large droplet (Ld-MaS) or small droplet (Sd-MaS) macrovesicular steatosis may coexist in the human liver, but the factors associated with the predominance of one type over the other, including hepatic fibrogenic capacity, are unknown. In pre-ischemic liver biopsies from 225 consecutive liver transplant donors, we retrospectively counted hepatocytes with Ld-MaS and Sd-MaS and defined the predominant type of steatosis as involving ≥50% of steatotic hepatocytes. We analyzed a donor Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphism, hepatic expression of proteins involved in lipid metabolism by RT-PCR, hepatic stellate cell (HSC) activation by α-SMA immunohistochemistry and, one year after transplantation, histological progression of fibrosis due to Hepatitis C Virus (HCV) recurrence. Seventy-four livers had no steatosis, and there were 98 and 53 with predominant Ld-MaS and Sd-MaS, respectively. In linear regression models, adjusted for many donor variables, the percentage of steatotic hepatocytes affected by Ld-MaS was inversely associated with hepatic expression of Insulin Induced Gene 1 (INSIG-1) and Niemann-Pick C1-Like 1 gene (NPC1L1) and directly with donor PNPLA3 variant M, HSC activation and progression of post-transplant fibrosis. In humans, Ld-MaS formation by hepatocytes is associated with abnormal PNPLA3-mediated lipolysis, downregulation of both the intracellular cholesterol sensor and cholesterol reabsorption from bile and increased hepatic fibrogenesis. Full article

(This article belongs to the Special Issue Molecular and Cellular Pathogenesis of Fatty Liver Disease and Its Progression)

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Review

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14 pages, 638 KiB

Open AccessReview

PD-1/PD-L1 Immuno-Mediated Therapy in NAFLD: Advantages and Obstacles in the Treatment of Advanced Disease

by Rosa Lombardi, Roberto Piciotti, Paola Dongiovanni, Marica Meroni, Silvia Fargion and Anna Ludovica Fracanzani

Int. J. Mol. Sci. 2022, 23(5), 2707; https://doi.org/10.3390/ijms23052707 - 28 Feb 2022

Cited by 10 | Viewed by 3541

Abstract

Non-alcoholic fatty liver disease (NAFLD) is characterized by an enhanced activation of the immune system, which predispose the evolution to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Resident macrophages and leukocytes exert a key role in the pathogenesis of NAFLD. In particular, CD4+ effector T cells are activated during the early stages of liver inflammation and are followed by the increase of natural killer T cells and of CD8+ T cytotoxic lymphocytes which contribute to auto-aggressive tissue damage. To counteract T cells activation, programmed cell death 1 (PD-1) and its ligand PDL-1 are exposed respectively on lymphocytes and liver cells’ surface and can be targeted for therapy by using specific monoclonal antibodies, such as of Nivolumab, Pembrolizumab, and Atezolizumab. Despite the combination of Atezolizumab and Bevacizumab has been approved for the treatment of advanced HCC, PD-1/PD-L1 blockage treatment has not been approved for NAFLD and adjuvant immunotherapy does not seem to improve survival of patients with early-stage HCC. In this regard, different ongoing phase III trials are testing the efficacy of anti-PD-1/PD-L1 antibodies in HCC patients as first line therapy and in combination with other treatments. However, in the context of NAFLD, immune checkpoints inhibitors may not improve HCC prognosis, even worse leading to an increase of CD8+PD-1+ T cells and effector cytokines which aggravate liver damage. Here, we will describe the main pathogenetic mechanisms which characterize the immune system involvement in NAFLD discussing advantages and obstacles of anti PD-1/PDL-1 immunotherapy. Full article

(This article belongs to the Special Issue Molecular and Cellular Pathogenesis of Fatty Liver Disease and Its Progression)

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