br Targeting LAL Neutral lipid esters
Targeting LAL Neutral lipid esters of two different sources may undergo α-CEHC hydrolysis: Neutral lipid esters, which derive from the endocytic pathway via the endocytosis of neutral lipid ester-rich lipoprotein particles (e.g. chylomicron remnants), or neutral lipid esters, which derive from cytosolic LDs and are engulfed from autophagosomes and fuse with lysosomes, undergo lysosomal degradation. The latter process is termed lipophagy (for recent reviews see [, , ]). Either way, the importance of acid hydrolysis of neutral lipid esters in lysosomes is evident from mutations in the LAL gene. Mutations with functional disruption of LAL activity are causative for autosomal recessive lysosomal storage disorders. Patients presenting complete disruption of LAL activity develop the more severe form of lysosomal storage disease, known as Wolman disease (OMIM #278000), and usually die within the first year . Patients with mutations in LAL, which retain residual LAL activity (1–12%, ), develop cholesteryl ester storage disease (OMIM #278000) and life until adulthood . General symptoms include CE and TAG accumulation in many tissues encompassing severe hepatic CE and TAG accumulation together with a yellowish and greasy appearance of the liver, hepatosplenomegaly, dyslipidemia/hyperlipidemia, and infiltration of lipid-filled Kupffer cells [147,150]. Fasting plasma dyslipidemia is characterized by increased TAG and LDL-cholesterol content, and accompanied by increased apolipoprotein-B levels, while HDL-cholesterol content is decreased, indicative for increased VLDL secretion [59,151]. In Wolman disease, secondary abnormalities due to chronic diarrhea and malabsorption may lead to a decline of fat in subcutaneous tissue [152,153]. Similar to affected humans, also Lal knockout mice exhibit massive CE and TAG accumulation in the liver and many other tissues, hepatosplenomegaly, proliferation of hepatocytes and Kupffer cells, and reduced survival [57,154,155]. Massive accumulation of CE in the liver leads to the formation of cholesterol crystals , which may disturb cellular integrity and induce an inflammatory response. Similar to patients, Lal knockout mice show increased plasma free FAs and LDL cholesterol levels, while HDL cholesterol level are decreased and total cholesterol and TAG levels are normal . More recently, LAL has been shown not only to degrade CE and TAG in lysosomes but also REs . However, LAL-deficient mice exhibit reduced and not increased hepatic RE content. This is likely a consequence of defective intestinal absorption/decreased nutritional availability of vitamin A, since LAL-deficient mice exhibit lower postprandial circulating RE levels. Furthermore, prolonged, 12 h-fasting of LAL-deficient mice led to reduced VLDL secretion and lowered plasma TAG levels . Reduced VLDL secretion after such prolonged fasting may be a result of diminished FA supply via the circulation because LAL-deficient mice exhibit a lipodystrophy-like phenotype, largely devoid of adipose tissue depots . On the other hand, reduced VLDL secretion upon fasting may also indicate defective lipophagy in these animals, since in the fasted state, liver lipophagy is thought to significantly contribute to FA supply as building blocks and as energy substrate . This view is supported by observations that inhibition of lysosomal activity upon chloroquine treatment lowers VLDL secretion of hepatocytes and murine liver [157,158] and that Atg7 knockout mice develop hepatosteatosis . Thus, the obvious defect in CE and TAG mobilization in liver and other tissues of LAL-deficient mice may suggest defective autophagy as cause for hepatic steatosis. However, it is difficult to dissociate between the contribution of i) lipoprotein-particle associated lipid uptake, ii) lipophagy of cytosolic LDs, and iii) impaired whole-body lipid supply as a consequence of progressive loss of adipose tissue in these mice [57,156]. Additionally, more recent studies have indicated that the lipophagy and lipopolytic pathway are apparently linked together via a process termed chaperon-mediated autophagy : LD-associated proteins, such as perilipins or ATGL, carry a canonical KFERQ motif, which allows the direct interaction with the protein 1A/1B-light chain 3 (LC3), which initiates the formation of autolysosomes and finally lipophagy [160,161]. Thus, in view of such interrelation between lipophagy and lipolysis, both processes obviously go hand-in-hand and, thus, their relative contributions is hard to assess.