Background And Aims: Steatotic liver disease (SLD) associated with insulin resistance (IR) and the metabolic syndrome ('IR-SLD') increases the risk of liver disease, type 2 diabetes and cardiovascular disease (CVD). SLD associated with the PNPLA3 I148M variant ('PNPLA3-SLD') also predisposes individuals to liver disease but protects against type 2 diabetes and CVD. Although in real life the two causes of SLD commonly co-exist, the opposite effects of 'IR-SLD' and 'PNPLA3-SLD' on CVD and liver disease suggest their pathogenesis differs.
Methods And Results: This review summarises human data comparing the effects of 'IR-SLD' and 'PNPLA3-SLD' on the human liver lipidome, hepatic handling of fatty acids, pathways of intrahepatocellular triglyceride synthesis, circulating lipids and lipoproteins and adipose tissue inflammation. We also discuss how steatosis in PNPLA3 I148M carriers leads to defects in mitochondrial function.
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