Mechanism and therapeutic strategy of hepatic TM6SF2-deficient non-alcoholic fatty liver diseases via in vivo and in vitro experiments

Abstract

BACKGROUND The lack of effective pharmacotherapies for nonalcoholic fatty liver disease (NAFLD) is mainly attributed to insufficient research on its pathogenesis. The pathogenesis of TM6SF2-efficient NAFLD remains unclear, resulting in a lack of therapeutic strategies for TM6SF2-deficient patients. AIM To investigate the role of TM6SF2 in fatty acid metabolism in the context of fatty liver and propose possible therapeutic strategies for NAFLD caused by TM6SF2 deficiency. METHODS Liver samples collected from both NAFLD mouse models and human participants (80 cases) were used to evaluate the expression of TM6SF2 by using western blotting, immunohistochemistry, and quantitative polymerase chain reaction. RNA-seq data retrieved from the Gene Expression Omnibus database were used to confirm the over-expression of TM6SF2. Knockdown and overexpression of TM6SF2 were performed to clarify the mechanistic basis of hepatic lipid accumulation in NAFLD. MK-4074 administration was used as a therapeutic intervention to evaluate its effect on NAFLD caused by TM6SF2 deficiency. RESULTS Hepatic TM6SF2 levels were elevated in patients with NAFLD and NAFLD mouse models. TM6SF2 overexpression can reduce hepatic lipid accumulation, suggesting a protective role for TM6SF2 in a high-fat diet (HFD). Downregulation of TM6SF2, simulating the TM6SF2 E167K mutation condition, increases intracellular lipid deposition due to dysregulated fatty acid metabolism and is characterized by enhanced fatty acid uptake and synthesis, accompanied by impaired fatty acid oxidation. Owing to the potential effect of TM6SF2 deficiency on lipid metabolism, the application of an acetyl-CoA carboxylase inhibitor (MK-4074) could reverse the NAFLD phenotypes caused by TM6SF2 deficiency. CONCLUSION TM6SF2 plays a protective role in the HFD condition; its deficiency enhanced hepatic lipid accumulation through dysregulated fatty acid metabolism, and MK-4074 treatment could alleviate the NAFLD phenotypes caused by TM6SF2 deficiency.

Investigating the role of lipid genes in liver disease using fatty liver models of alcohol and high fat in zebrafish (Danio rerio)

“…Loss of TM6SF2 function modulates hepatic lipid metabolism to produce significant changes in intracellular lipid accumulation 42 . Depleting TM6SF 2, which assists secretion of lipids in TG‐rich lipoprotein from lipid droplets, increases intracellular lipid deposition and is accompanied by enhanced fatty acid synthesis and impaired fatty acid oxidation in mice 8,42 . Our tm6sf2 gene depletion alone confirms this role by downregulating β‐oxidation with increased TG accumulation and further by increasing lipid synthesis in the presence of EtOH and HFD.…”

“…5,6 Recent studies indicate that specific gene mutations confer risk and might influence disease progression in some people to irreversible liver cirrhosis. [7][8][9][10] Our recent Genome-Wide Association Study (GWAS) in the GenomALC cohort of thousands of drinkers reported novel (FAF2, SERPINA1) and previously reported (PNPLA3, SUGP1/ TM6SF2, HSD17B13) associations of single nucleotide polymorphisms (SNPs) with risk of alcohol-and NAFLD-related cirrhosis. 7,11 Intriguingly, the novel FAF2 variant along with PNPLA3, HSD17B13 and SUGP1/TM6SF2 SNPs are all implicated in lipid biology.…”

Investigating the role of lipid genes in liver disease using fatty liver models of alcohol and high fat in zebrafish (Danio rerio)

“…[42] Knockdown of TM6SF2 which assists secretion of lipids in TG-rich lipoprotein from lipid droplets increases intracellular lipid deposition and is accompanied by enhanced fatty acid synthesis and impaired fatty acid oxidation in mice. [8,42] Our tm6sf2 knockdown alone confirms this role by downregulating b-oxidation with increased TG accumulation, and further by increasing lipid synthesis in the presence of EtOH and HFD.…”

“…[5,6] Recent studies indicate that specific gene mutations confer risk and might influence disease progression in some people to irreversible liver cirrhosis. [7][8][9][10] Our recent Genome-Wide Association Study (GWAS) in the GenomALC cohort of thousands of drinkers reported novel (FAF2, SERPINA1) and previously reported (PNPLA3, SUGP1/TM6SF2, HSD17B13) associations of single nucleotide polymorphisms (SNPs) with risk of alcohol-and NAFLDrelated cirrhosis. [7,11] Intriguingly, the novel FAF2 variant, along with PNPLA3, HSD17B13 and SUGP1/TM6SF2 SNPs, are all implicated in lipid biology.…”

Exploring the role of genetic variations in NAFLD: implications for disease pathogenesis and precision medicine approaches

“…The presence of multiple SNPs associated with NAFLD provides a more comprehensive understanding of the underlying genetic factors contributing to the disease. Furthermore, discussing the effect of different types of mutations on NAFLD can provide valuable insights into the genetic underpinnings of the disease and the identification of preventive and therapeutic strategies [ 12 ].…”