Novel Insights into the Genetic Landscape of Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD), the most common liver disorder worldwide, is epidemiologically associated with overweight, insulin resistance features and type 2 diabetes, and can progress to advanced liver fibrosis and hepatocellular carcinoma. Genetic factors play an important role in the development of NAFLD, which is a multifactorial disease. Several common naturally occurring variants modulating lipid and retinol metabolism in hepatocytes predispose to NAFLD development and progression, in particular those in PNPLA3, TM6SF2, MBOAT7, and HSD17B13. In addition, genetic variants that protect hepatic cells from oxidative stress modulate the susceptibility to progressive NAFLD. Although the molecular mechanisms linking these genetic variants with liver disease are not yet fully understood, hepatic fat has emerged as a major driver of the disease, while altered retinol metabolism and mitochondrial oxidative stress play a role in determining the development of advanced NAFLD

PNPLA3 I148M gene variant and chronic kidney disease in Type 2 diabetic patients with NAFLD: Clinical and experimental findings

Background & Aims Emerging evidence suggests an association between patatin‐like phospholipase domain‐containing protein‐3 (PNPLA3) rs738409 (I148M protein variant), and risk of chronic kidney disease (CKD), but the mechanisms underpinning this association are poorly understood. Methods We studied 157 patients with type 2 diabetes (T2DM) who underwent ultrasonography and vibration‐controlled transient elastography for diagnosing nonalcoholic fatty liver disease (NAFLD). CKD was defined as estimated glomerular filtration rate (e‐GFR) <60 ml/min/1.73m2 and/or abnormal albuminuria. We surveyed PNPLA3 mRNA expression in human tissues, using the liver as a positive control, and also measured PNPLA3 mRNA and protein expression levels in human cell lines represented in the kidney and the liver. Results 112 patients had NAFLD and 43 had CKD. Patients homozygous for the I148M variant (n=11) had lower e‐GFR levels (60.6±11.7 vs. 77.8±15.9 vs. 83.5±16.5 ml/min/1.73m2, p=0.0001) and higher prevalence of CKD (63.6% vs. 24.2% vs. 25.0%, p=0.028), compared to those with I/M (n=66) and I/I (n=80) PNPLA3 genotype. The association of I148M homozygosity with lower e‐GFR levels (p<0.0001) and higher risk of CKD (adjusted‐odds ratio 6.65; 95%CI 1.65‐26.8, p=0.008) was independent of liver disease severity (as detected by liver stiffness ≥7kPa) and other risk factors. PNPLA3 mRNA expression was greatest in liver and renal cortex, and podocytes showed high PNPLA3 mRNA and protein levels, comparable to that of hepatocytes and hepatic stellate cells, respectively. Conclusions The PNPLA3 I148M variant was associated with CKD, independently of common renal risk factors and severity of NAFLD. PNPLA3 expression levels were particularly high in renal podocytes