Purpose of review: To summarize recent research into the mechanisms linking insulin resistance, nonalcoholic fatty liver disease and metabolic dyslipidaemia.
Recent findings: Pathologically increased nonesterified fatty acids have widely been viewed as a key driver of hepatic insulin resistance/nonalcoholic fatty liver disease/metabolic dyslipidaemia. However, this may have been overestimated, and growing evidence now also implicates dysregulated hepatic de-novo lipogenesis in the pathogenesis of these phenomena. This is driven by the action of hyperinsulinaemia on the liver, mediated by PI3 kinase, though consensus on the downstream effectors remains to be reached. Endoplasmic reticulum stress and/or components of the attendant unfolded protein response have also emerged as players in dysregulated hepatic metabolism due to nutritional overload. Several points of convergence between metabolic and unfolded protein response pathways have been described, notably centring on the transcription factor XBP1.
Summary: Insulin resistance, nonalcoholic fatty liver disease and metabolic dyslipidaemia are inextricably linked and need to be considered together. Modelling and dissecting prevalent forms of the disease is complex, but unrestrained de-novo lipogenesis driven by hyperinsulinaemia appears to play an important role. Endoplasmic reticulum stress and the associated unfolded protein response may also contribute to cellular mismatch between triglyceride secretion/metabolism and synthesis, though a complete picture has yet to emerge.