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Article

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
1,*,
Simone Carotti
2,
Guido Carpino
3,
Monica Mischitelli
1,
Alfredo Cantafora
1,
Antonio Molinaro
4,
Maria Eva Argenziano
1,
Simona Parisse
1,
Alessandro Corsi
5,
Mara Riminucci
5,
Quirino Lai
6,
Gianluca Mennini
6,
Gustavo Spadetta
7,
Francesco Pugliese
7,
Massimo Rossi
6,
Sergio Morini
2,
Eugenio Gaudio
8 and
Stefano Ginanni Corradini
1
1
Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy
2
Laboratory of Microscopic and Ultrastructural Anatomy, CIR, University Campus Bio-Medico, 00128 Rome, Italy
3
Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome “Foro Italico”, 00135 Rome, Italy
4
Wallenberg Laboratory, Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden
5
Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
6
General Surgery and Organ Transplantation Unit, Department of Surgery, Sapienza University of Rome, 00161 Rome, Italy
7
Department of Internal Anesthesiological and Cardiovascular Clinical Sciences, Sapienza University of Rome, 00185 Rome, Italy
8
Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00161 Rome, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(11), 6100; https://doi.org/10.3390/ijms22116100
Submission received: 23 April 2021 / Revised: 28 May 2021 / Accepted: 3 June 2021 / Published: 5 June 2021
(This article belongs to the Special Issue Molecular and Cellular Pathogenesis of Fatty Liver Disease and Its Progression)
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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.
Keywords: cholesterol; liver donor; hepatic stellate cells; fibrosis; large droplet macrovesicular steatosis; lipid droplets; INSIG-1; NAFLD; NPC1L1; PNPLA3 cholesterol; liver donor; hepatic stellate cells; fibrosis; large droplet macrovesicular steatosis; lipid droplets; INSIG-1; NAFLD; NPC1L1; PNPLA3

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MDPI and ACS Style

Ferri, F.; Carotti, S.; Carpino, G.; Mischitelli, M.; Cantafora, A.; Molinaro, A.; Argenziano, M.E.; Parisse, S.; Corsi, A.; Riminucci, M.; et al. 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. Int. J. Mol. Sci. 2021, 22, 6100. https://doi.org/10.3390/ijms22116100

AMA Style

Ferri F, Carotti S, Carpino G, Mischitelli M, Cantafora A, Molinaro A, Argenziano ME, Parisse S, Corsi A, Riminucci M, et al. 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. International Journal of Molecular Sciences. 2021; 22(11):6100. https://doi.org/10.3390/ijms22116100

Chicago/Turabian Style

Ferri, Flaminia, Simone Carotti, Guido Carpino, Monica Mischitelli, Alfredo Cantafora, Antonio Molinaro, Maria Eva Argenziano, Simona Parisse, Alessandro Corsi, Mara Riminucci, and et al. 2021. "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" International Journal of Molecular Sciences 22, no. 11: 6100. https://doi.org/10.3390/ijms22116100

APA Style

Ferri, F., Carotti, S., Carpino, G., Mischitelli, M., Cantafora, A., Molinaro, A., Argenziano, M. E., Parisse, S., Corsi, A., Riminucci, M., Lai, Q., Mennini, G., Spadetta, G., Pugliese, F., Rossi, M., Morini, S., Gaudio, E., & Ginanni Corradini, S. (2021). 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. International Journal of Molecular Sciences, 22(11), 6100. https://doi.org/10.3390/ijms22116100

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