sLRP1ng Up Glucose: LRP1 Regulates Hepatic Insulin Responses

The “metabolic syndrome” is composed of an inter-related group of risk factors including dyslipidemia, obesity, elevated blood pressure, fatty liver, and elevated blood glucose levels. A common feature in these conditions is the dysregulation of metabolic processes. In this issue of eBioMedicine, Joachim Herz and colleagues demonstrate that loss of the LDL Receptor-Related Protein (LRP1) in the liver primes mice for a range of metabolic dysfunctions. These findings suggest that physiological actions of LRP1 normally serve to protect against development of the metabolic syndrome (Ding et al., 2016). LRP1 was first identified by Herz et al. in 1988 on the basis of its sequence homology with the LDL receptor (Herz et al., 1988). Consequently, much of the research into LRP1 function has been focused on lipid metabolism and its effects on atherosclerosis. In the liver, LRP1 clears the remnants of triglyceride-rich lipoproteins (chylomicrons and very low-density lipoproteins), after they have delivered their payload of triglyceride to peripheral tissues. In the endothelium, LRP1 has been linked to the intracellular transport of a range of cell-surface receptors, and this action has also been proposed to protect against the development and progression of atherosclerosis. Recently, a proteomics study identified LRP1 as a component of the glucose transporter regulatory vesicles in isolated adipocytes (Jedrychowski et al., 2010), suggesting that LRP1 may have a novel role regulating glucose metabolism. Based on this finding, Ding et al. hypothesized that liver-specific deletion of LRP1 in mice would reveal its importance in systemic glucose metabolism. The authors challenged control and liver-specific LRP1-deficient mice with a high-fat diet (60% of the calories derived from fat). Liverspecific LRP1 knockout mice had amarked loss of metabolic control relative to liter-mate controls. The knockout mice were obese, they had higher fasting glucose levels and reduced glucose clearance, and they had fatty liver. These phenotypes were linked with decreased VLDL secretion, and attenuated responses to insulin. Interestingly, when the authors probed hepatic insulin signaling they observed that the chowfed LRP1 knockout mice had more profound perturbations in insulin