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Fatty Liver Disease
Published in David Heber, Zhaoping Li, Primary Care Nutrition, 2017
It has been proposed that in those who have NAFLD without concomitant metabolic syndrome, the condition may originate from genetic susceptibility, while in those who have both NAFLD and metabolic syndrome, the conditions are due to a Western lifestyle and its consequences, obesity and insulin resistance. In the absence of metabolic syndrome, NAFLD does not increase the risk for developing type 2 diabetes mellitus in comparison with healthy subjects. The perception that there are different phenotypes of NAFLD and that the major division between the phenotypes is whether the NAFLD is combined with insulin resistance is founded on numerous studies, including genetic studies, some on a polymorphism of the PNPLA3 gene that is associated with NAFLD without metabolic syndrome (Speliotes et al. 2010; Shen et al. 2014; Lonardo et al. 2015a; Park et al. 2015; Petaja and Yki-Jarvinen 2016).
Dietary Carbohydrate Restriction in the Management of NAFLD and Metabolic Syndrome
Published in Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss, Nutrition and Cardiometabolic Health, 2017
Grace Marie Jones, Kathleen Mulligan, Jean-Marc Schwarz, Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss
Genome-wide association studies have identified loss-of-function gene variants that are involved in hepatic lipid metabolism and play a major role in the pathogenesis of NAFLD (Dongiovanni, Romeo et al. 2015). The I148M variant of the patatin-like phospholipase domain-containing 3 gene, PNPLA3 or adiponutrin, a lipase involved in the hydrolysis of triglycerides (Pingitore, Pirazzi et al. 2014), was strongly associated with increased fat levels and inflammation in the liver. Interestingly, Hispanics as a group are more susceptible to NAFLD and are more likely to have the I148M variant than African- or European-Americans (Romeo, Kozlitina et al. 2008). A second variant, E167K of the transmembrane 6 superfamily member 2 gene, was found in two separate studies (Holmen, Zhang et al. 2014, Kozlitina, Smagris et al. 2014) and has been shown to regulate hepatic lipid metabolism via VLDL secretion (Mahdessian, Taxiarchis et al. 2014). Additionally, the glucokinase regulator P446L polymorphism has a significant association with NAFLD and has been shown to increase DNL, liver fibrosis, and triglyceride levels (Speliotes, Yerges-Armstrong et al. 2011, Wu, Lemaitre et al. 2013, Petta, Miele et al. 2014, Aguilar-Olivos, Almeda-Valdes et al. 2015, Santoro, Caprio et al. 2015). Other genes involved in hepatic lipid metabolism, including FATP5, LYPLAL1, NCAN, PPAR, PPP1R3B, LPIN1, TRIB1, and UCP2,* have been implicated in the pathogenesis of NAFLD. However, further research is needed to clarify their suspected roles (Speliotes, Yerges-Armstrong et al. 2011, Kitamoto, Kitamoto et al. 2014).
PNPLA3 and IL 28B signature for predicting susceptibility to chronic hepatitis C infection and fibrosis progression
Published in Archives of Physiology and Biochemistry, 2022
Samar Samir Youssef, Eman Abd El Razek Abbas, Rana Ahmed Youness, Moustafa Nouh Elemeery, Amal Soliman Nasr, Sameh Seif
Since PNPLA3 has been identified as a genetic determinant of liver fibrosis in both NAFLD (He et al.2010, Estrabaud et al.2012, Manchiero et al.2017, Stattermayer et al.2017) and alcoholic liver disease’s patients (Romeo et al.2008, Rotman et al.2010, Tian et al.2010, Valenti et al.2010, Stickel et al.2011, Kawaguchi et al.2012), it was theorised that PNPLA3 SNP is also associated with steatosis and fibrosis progression in CHC patients (Trepo et al.2011, Valenti et al.2011). Although previous studies identified a positive association between the PNPLA3 genotype and steatosis or fibrosis progression in CHC patients (Trepo et al.2011, Valenti et al.2011). Through analysis, we proved that IL28B and PNPLA3 genotypes are independent predictors of rapid fibrosis progression in CHC patients. Thus, we had the unique chance to evaluate the association of IL28B and PNPLA3 genotypes with rapid fibrosis progression in CHC genotype 4.
Non-alcoholic fatty liver disease - opportunities for personalized treatment and drug development
Published in Expert Review of Precision Medicine and Drug Development, 2022
Aurino M. Kemas, Sonia Youhanna, Volker M. Lauschke
When successful, lifestyle interventions that include a Mediterranean diet and increased physical activity are highly effective in reducing body weight and ameliorating hepatic steatosis and inflammation [86]. For instance, histological analysis of liver biopsies from 293 patients with NASH showed that 138 (47%) had reductions in NAFLD activity score, 72 (25%) achieved resolution of NASH and 56 (19%) had regression of fibrosis after 52 weeks and weight loss was independently associated with improved NASH histology [87]. Subjects with carbohydrate-restricted diets (<20 g/d) showed significantly higher liver fat reduction than subjects on low-calorie diets (1,200–1,500 kcal/day) despite similar weight loss [88]. Furthermore, a recent 5-year longitudinal cohort study showed that glycemic control constituted an independent predictor for the progression of NASH-associated fibrosis [89]. Notably, carriers of the p.I148M (rs738409) risk variant in PNPLA3 experienced significantly higher loss in liver fat content in response to dietary interventions compared to non-carriers, suggesting that lifestyle modifications can counteract the effects of genetic predisposition [90,91].
What considerations are there for the pharmacotherapeutic management of nonalcoholic steatohepatitis?
Published in Expert Opinion on Pharmacotherapy, 2021
Masato Yoneda, Yasushi Honda, Satoru Saito, Atsushi Nakajima
A genome-wide association study (GWAS) of Hispanic, African American, and European American individuals published in 2008 [9] revealed that the genetic variation rs738409 (I148M) in PNPLA3 influences NAFLD. Since that report, many studies have shown that the variant of PNPLA3 rs738409 (148 M) is related to hepatic steatosis, inflammation, fibrosis, and even HCC in both NAFLD and alcoholic fatty liver patients. The frequency of the PNPLA3 (148 M) variant ranged from 17% in African Americans and 23% in European Americans to 49% among the Hispanic in the study [9]. PNPLA3 is a protein that is not yet fully understood, however, it plays a broad role in metabolic liver diseases from hepatic steatosis to cirrhosis and HCC. Variants with other Single Nucleotide Polymorphisms (SNPs), such as TM6SF2, MBOAT7, and GCKR, have been shown to contribute significantly to the pathogenesis of NAFLD as well [10]. As genetic factors are better understood, novel preventive and therapeutic strategies are expected to be developed for precise pharmaceutical approaches for NASH in the near future.