Emerging Metabolic and Transcriptomic Signature of PNPLA3‐Associated NASH

Abstract

A bout 30% of the adult population in the USA is afflicted with NAFLD. Approximately 20%-25% of patients with NAFLD have the progressive subtype of NAFLD: NASH. The cardinal features of NASH on liver histology include steatosis, lobular inflammation, and ballooning with or without perisinusoidal fibrosis. (1) Currently, NASH is the second-leading indication for liver transplant in the USA, and is the fastest rising etiology leading to rising rates of HCC in the USA. The mechanistic understanding of why some patients with NAFLD have a nonprogressive course, while others progress to NASH leading to cirrhosis and HCC, is unclear. Several genome-wide association studies have consistently shown that a single nucleotide polymorphism in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene, which changes isoleucine (I) to methionine (M) at residue 148 (rs738409 C>G polymorphism, PNPLA3 I148M ), is one of the strongest genetic risk factors for NAFLD progression. (2) PNPLA3 I148M is not only associated with greater risk of progressive steatohepatitis but also with cirrhosis and HCC. (3,4) Although PNPLA3 function has been studied extensively, the molecular mechanisms of how the I148M variant drives hepatic fibrosis and carcinogenesis remain unclear.To understand the mechanisms of PNPLA3 I148M in NASH pathogenesis, previous studies have generated transgenic and knock-in mice in C57BL/6J background that expressed either human or mouse PNPLA3 I148M variant. (5,6) When fed with high sucrose or high fat diet, the mice expressing PNPLA3 I148M variant quickly progressed to steatosis as compared with wild-type (PNPLA3 WT ) mice. However, the NASH and fibrosis phenotype was not apparent in these models. Therefore, although these studies provided key insights into the role of PNPLA3 I148M in steatosis development, how it modulates NASH and fibrosis progression remains to be further explored. In this issue of Hepatology, Banini et al. used a well-characterized diet-induced animal model of NAFLD (DIAMOND), which has been shown to sequentially develop steatosis, NASH, and fibrosis within 16 weeks on a high-fat (Western) diet with sugars in drinking water (WDSW ). 7 Mouse livers were transduced with adeno-associated virus-8 expressing human

PNPLA3-I148M Variant Promotes the Progression of Liver Fibrosis by Inducing Mitochondrial Dysfunction

“…In the last decade, an increasing number of events have demonstrated that PNPLA3 rs738409 polymorphism is closely associated with hepatic fat accumulation, ALD, NASH, cirrhosis, and HCC [15,17,[25][26][27][28]. It has been further reported that the PNPLA3-I148M variant promotes the progression of fibrosis by modulating retinol metabolism and upregulating the pro-inflammatory cytokines JNK and AP-1 in HSCs or LX-2 cells upon different types of nutritional status, respectively [20][21][22].…”

“…Increasing evidence has supported the notion that FC load is closely related to mitochondrial dysfunction in NASH [25,26]. On this basis, we further evaluated mitochondrial function in PNPLA3-I148I and -I148M stably expressed LX2 cells.…”

Single nucleotide polymorphisms in PNPLA3, ADAR-1 and IFIH1 are associated with advanced liver fibrosis in patients co-infected with HIV-1//hepatitis C virus

“…In our patient cohort, we found that the PNPLA3/rs738409 variant was significantly associated with liver fibrosis in unadjusted and adjusted models. The G allele of PNPLA3/rs738409 produces a mutation, I184 M. After activation of STAT3 (signature of transducer and activator of transcription 3), this allele is involved in the persistent inflammatory response associated with liver fat accumulation and NAFLD/NASH [21]. In a mouse model of NASH, development of steatohepatitis and fibrosis is accelerated and its severity worsened by overexpression of human PNPLA3I148 M [22].…”

Advances in genetic variation in metabolism-related fatty liver disease

“…While minimizing reliance on live animal models, the results show that I148M variants lead to increased lipid accumulation and susceptibility to hepatotoxins ( Tilson et al, 2021 ). Previous studies have demonstrated that PNPLA3(148M) variation is associated with a variety of liver diseases, including MAFLD, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) ( Dhar and Loomba, 2021 ), and increases the risk of liver-related death ( Grimaudo et al, 2020 ; Stender and Loomba, 2020 ). The genetic locus has been identified as having the most powerful role in increasing liver disease ( Shang and Mashek, 2020 ).…”