Hepatocellular Carcinoma Development in Nonalcoholic Fatty Liver Disease

( Luca Valenti ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Hepatocellular carcinoma (HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis,alcohol abuse, and exposure to hepatotoxins are major risk factors. Nonalcoholic fatty liver disease (NAFLD) associatedwith obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger of HCC, especially in developed countries.Indeed, NAFLD may already represent the first cause of liver disease underlying HCC development in the UK and USA.However, only a minority of NAFLD patients progresses to HCC. Older age, the severity of insulin resistance and in particularthe presence of type 2 diabetes, moderate alcohol intake, and iron overload have been reported to predispose to HCC in patientswith NAFLD. Remarkably, progressive NAFLD is a highly prevalent and mostly under-diagnosed condition, and it is frequentlyassociated with several metabolic comorbidities. Furthermore, HCC have been reported to develop in non-cirrhotic livers in amuch higher proportion of cases in NAFLD patients than in other etiologies. These factors render the implementation of currentsurveillance strategies very difficult for early diagnosis and curative treatment of NAFLD-HCC, leading to a diagnosis at advancestage a to a dismal prognosis in patients, with a reduced survival compared to that of patients affected by other liver diseases.Inherited factors have also been implicated to explain the different individual susceptibility to develop HCC, and their role seemsmagnified in NAFLD, where only a minority of affected subjects progresses to cancer. In particular, the common I148M variantof the PNPLA3 gene influencing hepatic lipid metabolism increases HCC risk independently of its effect on the progression ofliver fibrosis. However, common polymorphism in TM6SF2 and MBOAT7, and in familial cases mutations in APOB and TERT mayalso play a role.A deeper understanding of the mechanisms mediating hepatic carcinogenesis during insulin resistance - NAFLD, and the identificationof its genetic determinants will hopefully provide new diagnostic biomarkers to help stratifying disease risk and optimizesurveillance and highlight novel therapeutic targets.

Genetic Aspects of Non-obese NAFLD Patients

( Luca Valenti ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Epidemiological, familial, and twin studies indicate that non-alcoholic fatty liver disease (NAFLD), now the leading cause of liverdamage in developed countries, has a strong heritability. The common I148M variant of Patatin-like phospholipase domain-containg-3 (PNPLA3) impairing hepatocellular lipid droplets remodeling is the major genetic determinant of hepatic fat content.The I148M variant has a strong impact on the full spectrum of liver damage related to fatty liver, encompassing non-alcoholicsteatohepatitis, advanced fibrosis, and hepatocellular carcinoma, identifies a specific pathophysiological subtype of NAFLD, andinfluences the response to therapeutic approaches. Common variants in Glucokinase regulator (GCKR) also enhance de novohepatic lipogenesis in response to glucose and liver inflammation. Furthermore, the E167K variant of Transmembrane-6 superfamilymember-2 (TM6SF2) and the rs641738 non-coding polymorphism in the MBOAT7/TMC4 locus are associated with thedevelopment and progression of NAFLD, by altering lipidation of very-low density lipoproteins (VLDLs) and lipid secretion, andphosphatydil-inositol metabolism, respectively.Genetic factors seem to contribute to an even greater extent to the pathogenesis of NAFLD in non-obese individuals, compensatingfor less severe metabolic cofactors that may be less important. For example, in some studies the PNPLA3 I148M variant hasbeen reported to confer an even higher risk of disease than in obese subjects. Furthermore, rare mutations associated with severeloss-of-function of key proteins implicated in lipid metabolism are specifically associated with development of severe NAFLDin lean individuals. This is particularly true for mutations in Apolipoprotein B (APOB), which impair VLDLs secretion causing hepatocellularlipid retention and progressive liver disease, but at the same time may favor malnutrition by reducing fat absorptionby enterocytes. Furthermore, mutations in lysosomal acid lipase (encoded by LIPA) may cause early onset progressive liver diseaseand atherosclerosis related to defective degradation of cholesterol and triglycerides in hepatocytes independently of insulinresistance.These and other recent findings reviewed here indicate that impaired lipid handling by hepatocytes has a major role in the pathogenesisof NAFLD by triggering inflammation, fibrogenesis, and carcinogenesis. The role of the known genetic risk factors, andin particular those of rare variants with a strong phenotype, seems magnified in non-obese individuals, where metabolic determinantsare less severe. These discoveries have provided potential novel biomarkers for clinical use, in particular for NAFLD typizationin lean individuals, and have revealed intriguing therapeutic targets.

The I148M Variant of PNPLA3 Reduces the Response to Docosahexaenoic Acid in Children with Non-Alcoholic Fatty Liver Disease

Valerio Nobili,Giorgio Bedogni,Benedetta Donati,Anna Alisi,Luca Valenti 한국식품영양과학회 2013 Journal of medicinal food Vol.16 No.10

The aim of this secondary analysis of a randomized controlled trial was to test whether the I148M variant of Patatin-like phospholipase domain-containing protein-3 (PNPLA3) is associated with the response to docosahexaenoic acid (DHA) in children with non-alcoholic fatty liver disease (NAFLD). Sixty children with NAFLD were randomized in equal numbers to DHA 250 mg/day, DHA 500 mg/day or placebo. Coherently with the primary analysis, the probability of more severe steatosis after 24 months of DHA supplementation was 50% lower [95% confidence interval (CI) - 59% to - 42%)] in the combined DHA 250 and 500 mg/day groups versus placebo. The present secondary analysis revealed an independent effect of PNPLA3 status on the response to DHA. In fact, the probability of more severe steatosis was higher (37%, 95% CI 26– 48%) for the PNPLA3M/M versus I/M genotype and lower (- 12%, 95% CI - 21% to - 3%) for the I/I versus I/M genotype (Somers’ D for repeated measures). We conclude that the 148M allele of PNPLA3 is associated with lower response, and the 148I allele with greater response, to DHA supplementation in children with NAFLD.

Protective association of Klotho rs495392 gene polymorphism against hepatic steatosis in non-alcoholic fatty liver disease patients

Wen-Yue Liu,Xiaofang Zhang,Gang Li,Liang-Jie Tang,Pei-Wu Zhu,Rafael S. Rios,Kenneth I. Zheng,Hong-Lei Ma,Xiao-Dong Wang,Qiuwei Pan,Robert J. de Knegt,Luca Valenti,Mohsen Ghanbari,Ming-Hua Zheng 대한간학회 2022 Clinical and Molecular Hepatology(대한간학회지) Vol.28 No.2

Background/Aims: Non-alcoholic fatty liver disease (NAFLD) is closely associated with metabolic dysfunction. Among the multiple factors, genetic variation acts as important modifiers. Klotho, an enzyme encoded by the klotho (KL) gene in human, has been implicated in the pathogenesis of metabolic dysfunctions. However, the impact of variants in KL on NAFLD risk remains poorly understood. The aim of this study was to investigate the impact of KL rs495392 C>A polymorphism on the histological severity of NAFLD. Methods: We evaluated the impact of the KL rs495392 polymorphism on liver histology in 531 Chinese with NAFLD and replicated that in the population-based Rotterdam Study cohort. The interactions between the rs495392, vitamin D, and patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 polymorphism were also analyzed. Results: Carriage of the rs495392 A allele had a protective effect on steatosis severity (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.42–0.89; P=0.010) in Chinese patients. After adjustment for potential confounders, the A allele remained significant with a protective effect (OR, 0.66; 95% CI, 0.45–0.98; P=0.040). The effect on hepatic steatosis was confirmed in the Rotterdam Study cohort. Additional analysis showed the association between serum vitamin D levels and NAFLD specifically in rs495392 A allele carriers, but not in non-carriers. Moreover, we found that the rs495392 A allele attenuated the detrimental impact of PNPLA3 rs738409 G allele on the risk of severe hepatic steatosis. Conclusions: The KL rs495392 polymorphism has a protective effect against hepatic steatosis in patients with NAFLD.