Protein phosphatase 1 regulatory subunit 3B gene variation protects against hepatic fat accumulation and fibrosis in individuals at high risk of nonalcoholic fatty liver disease

Paola Dongiovanni, Marica Meroni, Rosellina M Mancina, Guido Baselli, Raffaela Rametta, Serena Pelusi, Ville Männistö, Anna L Fracanzani, Sara Badiali, Luca Miele, Stefania Grimaudo, Salvatore Petta, Elisabetta Bugianesi, Giorgio Soardo, Silvia Fargion, Jussi Pihlajamäki, Stefano Romeo, Luca Valenti

Research output: Contribution to journalArticle

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver damage and has a strong genetic component. The rs4841132 G>A variant, modulating the expression of protein phosphatase 1 regulatory subunit 3B (PPP1R3B), which is involved in glycogen synthesis, has been reported to reduce the risk of NAFLD but at the same time may favor liver disease by facilitating glycogen accumulation. The aim of this study was to assess the impact of rs4841132 on development of histologic steatosis and fibrosis in 1,388 European individuals in a liver biopsy cohort, on NAFLD hepatocellular carcinoma in a cross-sectional Italian cohort (n = 132 cases), and on liver disease at the population level in the United Kingdom Biobank cohort. We investigated the underlying mechanism by examining the impact of the variant on gene expression profiles. In the liver biopsy cohort, the rs4841132 minor A allele was associated with protection against steatosis (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.42-0.95; P = 0.03) and clinically significant fibrosis (OR, 0.35; 95% CI, 0.14-0.87; P = 0.02) and with reduced circulating cholesterol (P = 0.02). This translated into protection against hepatocellular carcinoma development (OR, 0.22; 95% CI, 0.07-0.70; P = 0.01). At the population level, the rs4841132 variation was not associated with nonalcoholic or nonviral diseases of the liver but was associated with lower cholesterol (P = 1.7 × 10-8). In individuals with obesity, the A allele protecting against steatosis was associated with increased PPP1R3B messenger RNA expression and activation of lipid oxidation and with down-regulation of pathways related to lipid metabolism, inflammation, and cell cycle. Conclusion: The rs4841132 A allele is associated with protection against hepatic steatosis and fibrosis in individuals at high risk of NAFLD but not in the general population and against dyslipidemia. The mechanism may be related to modulation of PPP1R3B expression and hepatic lipid metabolism. (Hepatology Communications 2018;2:666-675).

Original languageEnglish
Pages (from-to)666-675
Number of pages10
JournalHepatology communications
Volume2
Issue number6
DOIs
Publication statusPublished - 2018

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Protein Phosphatase 1
Fibrosis
Fats
Liver
Liver Diseases
Genes
Alleles
Odds Ratio
Confidence Intervals
Glycogen
Lipid Metabolism
Hepatocellular Carcinoma
Population
Biopsy
Gastroenterology
Dyslipidemias
Transcriptome
Cell Cycle
Down-Regulation
Obesity

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Protein phosphatase 1 regulatory subunit 3B gene variation protects against hepatic fat accumulation and fibrosis in individuals at high risk of nonalcoholic fatty liver disease. / Dongiovanni, Paola; Meroni, Marica; Mancina, Rosellina M; Baselli, Guido; Rametta, Raffaela; Pelusi, Serena; Männistö, Ville; Fracanzani, Anna L; Badiali, Sara; Miele, Luca; Grimaudo, Stefania; Petta, Salvatore; Bugianesi, Elisabetta; Soardo, Giorgio; Fargion, Silvia; Pihlajamäki, Jussi; Romeo, Stefano; Valenti, Luca.

In: Hepatology communications, Vol. 2, No. 6, 2018, p. 666-675.

Research output: Contribution to journalArticle

Dongiovanni, Paola ; Meroni, Marica ; Mancina, Rosellina M ; Baselli, Guido ; Rametta, Raffaela ; Pelusi, Serena ; Männistö, Ville ; Fracanzani, Anna L ; Badiali, Sara ; Miele, Luca ; Grimaudo, Stefania ; Petta, Salvatore ; Bugianesi, Elisabetta ; Soardo, Giorgio ; Fargion, Silvia ; Pihlajamäki, Jussi ; Romeo, Stefano ; Valenti, Luca. / Protein phosphatase 1 regulatory subunit 3B gene variation protects against hepatic fat accumulation and fibrosis in individuals at high risk of nonalcoholic fatty liver disease. In: Hepatology communications. 2018 ; Vol. 2, No. 6. pp. 666-675.
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title = "Protein phosphatase 1 regulatory subunit 3B gene variation protects against hepatic fat accumulation and fibrosis in individuals at high risk of nonalcoholic fatty liver disease",
abstract = "Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver damage and has a strong genetic component. The rs4841132 G>A variant, modulating the expression of protein phosphatase 1 regulatory subunit 3B (PPP1R3B), which is involved in glycogen synthesis, has been reported to reduce the risk of NAFLD but at the same time may favor liver disease by facilitating glycogen accumulation. The aim of this study was to assess the impact of rs4841132 on development of histologic steatosis and fibrosis in 1,388 European individuals in a liver biopsy cohort, on NAFLD hepatocellular carcinoma in a cross-sectional Italian cohort (n = 132 cases), and on liver disease at the population level in the United Kingdom Biobank cohort. We investigated the underlying mechanism by examining the impact of the variant on gene expression profiles. In the liver biopsy cohort, the rs4841132 minor A allele was associated with protection against steatosis (odds ratio [OR], 0.63; 95{\%} confidence interval [CI], 0.42-0.95; P = 0.03) and clinically significant fibrosis (OR, 0.35; 95{\%} CI, 0.14-0.87; P = 0.02) and with reduced circulating cholesterol (P = 0.02). This translated into protection against hepatocellular carcinoma development (OR, 0.22; 95{\%} CI, 0.07-0.70; P = 0.01). At the population level, the rs4841132 variation was not associated with nonalcoholic or nonviral diseases of the liver but was associated with lower cholesterol (P = 1.7 × 10-8). In individuals with obesity, the A allele protecting against steatosis was associated with increased PPP1R3B messenger RNA expression and activation of lipid oxidation and with down-regulation of pathways related to lipid metabolism, inflammation, and cell cycle. Conclusion: The rs4841132 A allele is associated with protection against hepatic steatosis and fibrosis in individuals at high risk of NAFLD but not in the general population and against dyslipidemia. The mechanism may be related to modulation of PPP1R3B expression and hepatic lipid metabolism. (Hepatology Communications 2018;2:666-675).",
author = "Paola Dongiovanni and Marica Meroni and Mancina, {Rosellina M} and Guido Baselli and Raffaela Rametta and Serena Pelusi and Ville M{\"a}nnist{\"o} and Fracanzani, {Anna L} and Sara Badiali and Luca Miele and Stefania Grimaudo and Salvatore Petta and Elisabetta Bugianesi and Giorgio Soardo and Silvia Fargion and Jussi Pihlajam{\"a}ki and Stefano Romeo and Luca Valenti",
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T1 - Protein phosphatase 1 regulatory subunit 3B gene variation protects against hepatic fat accumulation and fibrosis in individuals at high risk of nonalcoholic fatty liver disease

AU - Dongiovanni, Paola

AU - Meroni, Marica

AU - Mancina, Rosellina M

AU - Baselli, Guido

AU - Rametta, Raffaela

AU - Pelusi, Serena

AU - Männistö, Ville

AU - Fracanzani, Anna L

AU - Badiali, Sara

AU - Miele, Luca

AU - Grimaudo, Stefania

AU - Petta, Salvatore

AU - Bugianesi, Elisabetta

AU - Soardo, Giorgio

AU - Fargion, Silvia

AU - Pihlajamäki, Jussi

AU - Romeo, Stefano

AU - Valenti, Luca

PY - 2018

Y1 - 2018

N2 - Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver damage and has a strong genetic component. The rs4841132 G>A variant, modulating the expression of protein phosphatase 1 regulatory subunit 3B (PPP1R3B), which is involved in glycogen synthesis, has been reported to reduce the risk of NAFLD but at the same time may favor liver disease by facilitating glycogen accumulation. The aim of this study was to assess the impact of rs4841132 on development of histologic steatosis and fibrosis in 1,388 European individuals in a liver biopsy cohort, on NAFLD hepatocellular carcinoma in a cross-sectional Italian cohort (n = 132 cases), and on liver disease at the population level in the United Kingdom Biobank cohort. We investigated the underlying mechanism by examining the impact of the variant on gene expression profiles. In the liver biopsy cohort, the rs4841132 minor A allele was associated with protection against steatosis (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.42-0.95; P = 0.03) and clinically significant fibrosis (OR, 0.35; 95% CI, 0.14-0.87; P = 0.02) and with reduced circulating cholesterol (P = 0.02). This translated into protection against hepatocellular carcinoma development (OR, 0.22; 95% CI, 0.07-0.70; P = 0.01). At the population level, the rs4841132 variation was not associated with nonalcoholic or nonviral diseases of the liver but was associated with lower cholesterol (P = 1.7 × 10-8). In individuals with obesity, the A allele protecting against steatosis was associated with increased PPP1R3B messenger RNA expression and activation of lipid oxidation and with down-regulation of pathways related to lipid metabolism, inflammation, and cell cycle. Conclusion: The rs4841132 A allele is associated with protection against hepatic steatosis and fibrosis in individuals at high risk of NAFLD but not in the general population and against dyslipidemia. The mechanism may be related to modulation of PPP1R3B expression and hepatic lipid metabolism. (Hepatology Communications 2018;2:666-675).

AB - Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver damage and has a strong genetic component. The rs4841132 G>A variant, modulating the expression of protein phosphatase 1 regulatory subunit 3B (PPP1R3B), which is involved in glycogen synthesis, has been reported to reduce the risk of NAFLD but at the same time may favor liver disease by facilitating glycogen accumulation. The aim of this study was to assess the impact of rs4841132 on development of histologic steatosis and fibrosis in 1,388 European individuals in a liver biopsy cohort, on NAFLD hepatocellular carcinoma in a cross-sectional Italian cohort (n = 132 cases), and on liver disease at the population level in the United Kingdom Biobank cohort. We investigated the underlying mechanism by examining the impact of the variant on gene expression profiles. In the liver biopsy cohort, the rs4841132 minor A allele was associated with protection against steatosis (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.42-0.95; P = 0.03) and clinically significant fibrosis (OR, 0.35; 95% CI, 0.14-0.87; P = 0.02) and with reduced circulating cholesterol (P = 0.02). This translated into protection against hepatocellular carcinoma development (OR, 0.22; 95% CI, 0.07-0.70; P = 0.01). At the population level, the rs4841132 variation was not associated with nonalcoholic or nonviral diseases of the liver but was associated with lower cholesterol (P = 1.7 × 10-8). In individuals with obesity, the A allele protecting against steatosis was associated with increased PPP1R3B messenger RNA expression and activation of lipid oxidation and with down-regulation of pathways related to lipid metabolism, inflammation, and cell cycle. Conclusion: The rs4841132 A allele is associated with protection against hepatic steatosis and fibrosis in individuals at high risk of NAFLD but not in the general population and against dyslipidemia. The mechanism may be related to modulation of PPP1R3B expression and hepatic lipid metabolism. (Hepatology Communications 2018;2:666-675).

U2 - 10.1002/hep4.1192

DO - 10.1002/hep4.1192

M3 - Article

C2 - 29881818

VL - 2

SP - 666

EP - 675

JO - Hepatology communications

JF - Hepatology communications

SN - 2471-254X

IS - 6

ER -