Gene Variants Implicated in Steatotic Liver Disease: Opportunities for Diagnostics and Therapeutics - PubMed (original) (raw)

Review

Gene Variants Implicated in Steatotic Liver Disease: Opportunities for Diagnostics and Therapeutics

Gary Huang et al. Biomedicines. 2023.

Abstract

Non-alcoholic fatty liver disease (NAFLD) describes a steatotic (or fatty) liver occurring as a consequence of a combination of metabolic, environmental, and genetic factors, in the absence of significant alcohol consumption and other liver diseases. NAFLD is a spectrum of conditions. Steatosis in the absence of inflammation is relatively benign, but the disease can progress into more severe forms like non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. NAFLD onset and progression are complex, as it is affected by many risk factors. The interaction between genetic predisposition and other factors partially explains the large variability of NAFLD phenotype and natural history. Numerous genes and variants have been identified through large-scale genome-wide association studies (GWAS) that are associated with NAFLD and one or more subtypes of the disease. Among them, the largest effect size and most consistent association have been patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), and membrane-bound O-acyltransferase domain containing 7 (MBOAT7) genes. Extensive in vitro and in vivo studies have been conducted on these variants to validate these associations. The focus of this review is to highlight the genetics underpinning the molecular mechanisms driving the onset and progression of NAFLD and how they could potentially be used to improve genetic-based diagnostic testing of the disease and develop personalized, targeted therapeutics.

Keywords: MASH; MASLD; NAFLD; NASH; genetics; lipid metabolism; steatotic liver disease; variants.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

NAFLD progression. Damage from liver steatosis, NASH and early fibrosis are potentially reversible with treatment. However, damage resulting in cirrhosis is not typically reversible [15]. This figure was adapted to include new NAFLD nomenclature.

Figure 2

Figure 2

Examples of risk factors contributing to the promotion of NASH onset according to the multiple-hit hypothesis. Risk factors for NASH can be categorised into environmental, metabolic, and genetic, and their interactions with each other are presented in a Venn diagram.

Figure 3

Figure 3

Overview of lipid metabolism. Dietary carbohydrates and lipids are major contributors of fatty acids. Carbohydrates may be converted into triglycerides via the G3P pathway or fatty acids via DNL through the mitochondrial tricarboxylic acid cycle. The latter is regulated by both the ChREBP and SREBP1c signalling pathways. Fatty acids can be stored in cytoplasmic lipid droplets until required or be oxidised for removal. β-oxidation of lipids can occur in the mitochondria or peroxisomes and is mainly regulated by the PPARα signalling pathway. This figure was created with BioRender.com.

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