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. Author manuscript; available in PMC: 2015 Aug 5.
Published in final edited form as: Cell Metab. 2014 Jun 12;20(2):267–279. doi: 10.1016/j.cmet.2014.05.003

Figure 7. Proposed Role of Lipin-1 in Regulation of Lipid Levels, Autophagy Clearance, and Protection Against Statin Myotoxicity.

Figure 7

Left, In wild-type muscle, lipin-1 converts PA to DAG, providing substrate for TAG synthesis and activating PKD, with subsequent activation of Vps34 during autolysosome assembly. These steps allow normal autophagy flux. Right, In lipin-1 deficiency (red arrows and lines), the lipin-1 enzyme substrate, PA, accumulates and DAG levels are reduced. This causes impaired TAG synthesis, reduced PKD/Vps34 activation (active forms signified by asterisk), and reduced autophagic flux. Statin treatment has similar effects as lipin-1 deficiency at some points (blue arrows and lines). Statins cause increased PA accumulation and reduced PKD activation both in wild-type and lipin-1–haploinsufficient backgrounds. In addition, statin treatment in combination with lipin-1-haploinsufficiency or lipin-1 deficiency causes reduced mTOR activation, and autophagy initiation. The net result of statin treatment and reduced lipin-1 activity is to increase autophagy initiation, but prevent optimal flux through the pathway, leading to impaired autophagy clearance.