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Insulin signaling in the liver affects lipid synthesis and uptake in many ways. Two new papers by Ai et al. in the Journal of Clinical Investigation show how an insulin-regulated signaling protein complex, mTORC1, acts to promote both lipoprotein secretion and uptake (doi:10.1172/JCI61248; 122, 1262–1270).

In the first paper, the authors showed in genetic or dietary mouse models of obesity that mTORC1 promotes secretion of apoB, the major apolipoprotein of the atherogenic lipoproteins very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL). Activation of hepatic mTORC1 triggers an endoplasmic reticulum stress response, and the researchers found that an effector of this pathway, the transcription factor Atf3, directly represses expression of the protein sortilin-1. This protein is involved in the intracellular trafficking of secreted proteins from the Golgi to lysosomes. It has previously been linked by genome-wide association studies in humans to LDL cholesterol levels and the risk of myocardial infarction and has also been reported to negatively regulate hepatic VLDL secretion in mice.

In the second paper, the authors showed that the effect of mTORC1 on lipoprotein uptake goes through a separate pathway involving the protein PCSK9, whose expression mTORC1 controls by signaling through the transcription factor HNF-1α. PCSK9, which like sortilin-1 is involved in intracellular protein trafficking, is thought to divert LDL receptor recycling into an endosomal-lysosomal pathway that leads to LDL receptor degradation. PCSK9 is known to affect LDL receptor function in humans: individuals with PCSK9 mutations have high LDL receptor levels and low LDL cholesterol levels.