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)

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

“…This GCKR variant is also highly associated with fatty liver in obese youths [33]. Recent genetic and epidemiological studies have identified other polymorphisms associated with NAFLD progression in several genes involved in retinol metabolism (hydroxysteroid 17-beta dehydrogenase 3 (HSD17B3)), glycogen synthesis (protein phosphatase 1 regulatory subunit 3B (PPP1R3B)), bile acid homeostasis (beta-klotho (KLB)), oxidative stress (uncoupling protein 2 (UCP2), superoxide dismutase 2 (SOD2)), insulin signaling pathway (tribbles pseudokinase 1 (TRIB1)), and inflammation (suppressor of cytokine signaling 1 (SOCS1), interferon lambda 3 (IFNL3), MER proto-oncogene tyrosine kinase (MERTK)) [12,[34][35][36][37][38][39]. In addition, epigenetic mechanisms, including post-translational histone modifications, DNA methylation, and micro-RNAs, are important in disease development [12].…”

Nutrition and Genetics in NAFLD: The Perfect Binomium

“…Finally, the rs4841132 G>A variant, enhancing the expression of Protein Phosphatase 1 Regulatory subunit 3B (PPP1R3B), which is involved in glycogen synthesis, has been recently reported to reduce the risk of NAFLD, but at the same time, may favor liver disease by facilitating glycogen accumulation [96,97]. Conversely, in a rodent model, hepatic genetic deletion of PPP1R3B significantly reduced glycogen synthase protein abundance, glucose incorporation into hepatic glycogen, total hepatic glycogen content and fasting plasma glucose compared to wild-type littermates [98].…”

Diagnostic and interventional circulating biomarkers in nonalcoholic steatohepatitis

“…91,92 Similarly, a gene variation at the protein phosphatase 1 regulatory subunit 3b (PPP1R3B) is thought to potentially protect against hepatic fat accumulation and decreases risk of progressive liver disease in patients at high risk for NASH. 93,94 Lastly, the rs12979850 polymorphism in the IFNλ3 gene that participates in regulation of innate immunity has been associated with increased hepatic inflammation and fibrosis in patients with NAFLD, particularly in lean NAFLD. 95,96 Several genetic risk scores have been designed to predict the presence of NASH, NASH with fibrosis and NAFLD-related HCC.…”