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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 as a therapeutic target for fatty liver disease: the evidence to date
Published in Expert Opinion on Therapeutic Targets, 2021
Alessandro Cherubini, Elia Casirati, Melissa Tomasi, Luca Valenti
Despite the high prevalence of NAFLD, we still have a limited knowledge of the biological mechanisms involved in disease progression [7]. Indeed, NAFLD represents a multifactorial disease triggered by environmental stressors related to unhealthy lifestyle and diet. These triggers lead to increased adiposity, development of insulin resistance and diabetes, and synergize with genetic predisposition and epigenetic modifiers to induce liver disease [8]. In the last years it has been shown that changes in the gut bacterial microbiome may also contribute to NAFLD pathogenesis [9–11]. The heritability of NAFLD and hepatic fat accumulation are large generally estimated between 20 and 70%, depending on the ethnicity, the study design, and methodology used to investigate it [12]. Among the specific genetic risk variants, the patatin-like phospholipase domain–containing 3 (PNPLA3) rs738409 C>G single nucleotide polymorphism (SNP), encoding for p.I148M protein variation, has been widely demonstrated to represent the main genetic risk variant for hepatic fat accumulation, NAFLD and other forms of fatty liver disease, including alcoholic liver disease. At the same time, this variant represents a main determinant of NAFLD progression to cirrhosis and HCC [13–16].
Chorioretinal dystrophy, hypogonadotropic hypogonadism, and cerebellar ataxia: Boucher-Neuhauser syndrome due to a homozygous (c.3524C>G (p.Ser1175Cys)) variant in PNPLA6 gene
Published in Ophthalmic Genetics, 2021
Mustafa Doğan, Recep Eröz, Emrah Öztürk
PNPLA6 (Patatin-like phospholipase domain containing 6) consists of 34 exons on chromosome 19p13.2 and encodes a phospholipase enzyme called neuropathy target esterase (NTE) (NM_001166111.2). It is a highly conserved phospholipase that deacetylates intracellular phosphatidylcholine to produce glycerophosphocholine and is involved in the development of axons in the brain, eye, and pituitary gland (1). Hufnagel et al. examined PNPLA6 expression during both human central nervous system and retinal development and revealed PNPLA6 expression in embryonic tissues of the developing brain, neural retina, retinal pigment epithelium, choroid, anterior and posterior pituitary, cerebellum, and ventricular regions (2). NTE as an enzyme involved in lipid metabolism that is critical to the stability of cell membranes. Mutations in this region can disrupt the enzymatic activity of the PNPLA6 protein, which can impair the formation of synaptic connections in neuronal networks and intercellular interactions with cellular organelles (3). When a mutation occurred, it can cause a spectrum of disorders that range from intellectual disabilities to ataxia in humans (4). However, little has been revealed about the structure–function relationships between the domains of the NTE protein, its enzymatic activity, and interactions with cellular organelles (5). Symptoms and clinical findings of the patients with Boucher-Neuhäuser syndrome(BNHS) are given in Table 1.
Drug development of nonalcoholic fatty liver disease: challenges in research, regulatory pathways, and study endpoints
Published in Expert Opinion on Drug Discovery, 2021
Albert Do, Ysabel C. Ilagan-Ying, Wajahat Z. Mehal, Joseph K. Lim
In addition, the natural history of NASH is heterogeneous with variable rates of fibrosis progression. An estimated 15% to 20% of patients with NASH develop cirrhosis, with 4% with clinically compensated cirrhosis suffering decompensation per year [48,49]. Distinguishing those at risk for advanced fibrosis or cirrhosis could allow patient sample enrichment for clinical trial enrollment. Demographic and genetic factors may also contribute to the heterogeneity of NASH outcomes. Increasing age, male gender, and Hispanic or Asian ethnicity have been associated with higher prevalence of NASH and risk of fibrosis [20,50]. Variation in certain genetic polymorphisms such as mutation in the patatin-like phospholipase domain containing protein 3 (PNPLA3) gene have been associated with more severe disease independent of dietary factors or comorbid metabolic disease [51,52]. Genome-wide association studies (GWAS) have identified other genetic loci which modify risk for hepatic steatosis and fibrosis, including the transmembrane 6 superfamily member 2 (TM6SF2), membrane bound O-acyl-transferase domain-containing 7 (MBOAT7), and 17-beta hydroxysteroid dehydrogenase 13 (HSD17813) genes [53,54]. Further research on these genetic factors and their phenotypic expression in NAFLD, coupled with genetic data collection during clinical trials will help determine the role of genotype testing in NASH outcomes studies.