Hyperinsulinaemia: does it tip the balance toward intrahepatic fat accumulation?

Abstract

In health, the liver is metabolically flexible over the course of the day, as it undertakes a multitude of physiological processes including the regulation of intrahepatic and systemic glucose and lipid levels. The liver is the first organ to receive insulin and through a cascade of complex metabolic processes, insulin not only plays a key role in the intrahepatic regulation of glucose and lipid metabolism, but also in the regulation of systemic glucose and lipid concentrations. Thus, when intrahepatic insulin signalling becomes aberrant then this may lead to perturbations in intrahepatic metabolic processes that have the potential to impact on metabolic health. For example, obesity is associated with intrahepatic fat accumulation (known as nonalcoholic liver disease (NAFLD)) and hyperinsulinaemia, the latter as a result of insulin hypersecretion or impaired hepatic insulin extraction. Although insulin signalling directly alters intra- and extrahepatic metabolism, the regulation of hepatic glucose and fatty acid metabolism is also indirectly driven by substrate availability. Here we discuss the direct and indirect effects of insulin on intrahepatic processes such as the synthesis of fatty acids and peripherally regulating the flux of fatty acids to the liver; processes that may play a role in the development of insulin resistance and/or intrahepatocellular triacylglycerol (IHTAG) accumulation in humans.

Keywords: adipose tissue; de novo lipogenesis; insulin; liver.

Figure 1

Overview of insulin regulation on intrahepatic pathways in the postprandial state in healthy (A) and individuals with NAFLD or defined as insulin resistant (B). In the fasting state non-esterified fatty acids (NEFA) from the lipolysis of subcutaneous and visceral adipose tissue enter the liver and mix with fatty acids (FAs) from the cytosolic triacylglycerol (TAG) storage pool and those from de novo lipogenesis (DNL). FAs are then preferentially partitioned toward the oxidation pathway where the acetyl Co-A produced can enter the tricarboxylic acid cycle to produce CO₂ or ketogenic pathway, where the ketone bodies 3-hydroxybutyrate and acetoacetate are produced. FAs are also esterified to TAG and utilised in the production of very low-density lipoprotein (VLDL) particles. In the transition to the postprandial state, and after consumption of a mixed meal, FAs from the diet also enter the liver and mix with endogenous sources. The postprandial increase in plasma insulin concentrations suppresses adipose tissue lipolysis, decreasing the flux of NEFA to the liver. Within the liver, insulin upregulates the DNL pathway, leading to suppression in FA oxidation, VLDL production and secretion, and gluconeogenesis. Thus, during the postprandial period, cellular metabolism rapidly shifts away from energy supply to energy storage (A) and back again. In individuals with an ‘unhealthy’ phenotype (e.g. NAFLD, insulin resistance) the postprandial increase in plasma insulin concentrations will not suppress adipose tissue lipolysis to the same extent as in a ‘healthy’ individual, leading to a higher flux of NEFA to the intrahepatic FA pool. Within the liver, insulin will further upregulate the DNL pathway, leading to a greater contribution of FA to the FA pool, FA oxidation will be suppressed, and ceramide production may be increased, whilst VLDL production and secretion and gluconeogenesis are not attenuated. During the postprandial period in these individuals FAs will partitioned toward esterification pathways and utilised in the production of VLDL particles or stored in the cytosolic TAG storage pool rather than entering oxidation pathways (B).