Hormone-sensitive lipase : control of intracellular tri-( di-) acylglycerol and cholesteryl ester hydrolysis

Hormone-sensitive lipase (HSL) is an intracellular neutral lipase that is capable of hydrolyzing triacylglycerols, diacylglycerols, monoacylglycerols, and cholesteryl esters, as well as other lipid and water soluble substrates. HSL activity is regulated post-translationally by phosphorylation and also by pretranslational mechanisms. The enzyme is highly expressed in adipose tissue and steroidogenic tissues, with lower amounts expressed in cardiac and skeletal muscle, macrophages, and islets. Studies of the structure of HSL have identified several amino acids and regions of the molecule that are critical for enzymatic activity and regulation of HSL. This has led to important insights into its function, including the interaction of HSL with other intracellular proteins, such as adipocyte lipid binding protein. Accumulating evidence has defined important functions for HSL in normal physiology, affecting adipocyte lipolysis, steroidogenesis, spermatogenesis, and perhaps insulin secretion and insulin action; however, direct links between abnormal expression or genetic variations of HSL and human disorders, such as obesity, insulin resistance, type 2 diabetes, and hyperlipidemia, await further clarification. The published reports examining the regulation, and function of HSL in normal physiology and disease are reviewed in this paper. —Kraemer, F. B. , and W-J. Shen. Hormone-sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis. J. Lipid Res. 2002. 43: 1585–1594. Supplementary key words lipolysis • free fatty acids • adipose • adrenal • macrophage • testis • islet Hormone-sensitive lipase (HSL) activity was first identified as an epinephrine-sensitive lipolytic activity in adipose tissue. Its name was coined to reflect the ability of hormones such as catecholamines, ACTH, and glucagon to stimulate the activity of this intracellular neutral lipase (1). Hormonal activation of HSL occurs via cyclic AMP dependent protein kinase (PKA), which phosphorylates HSL (2). As the enzyme responsible for the release of free fatty acids (FFA) from adipose tissue, HSL is felt to play a pivotal role in providing the major source of energy for most tissues. Although its expression is highest in adipose tissue, HSL is also expressed in adrenal, ovary, testis, and to a lesser extent in skeletal and cardiac muscle and macrophages (3, 4). Following the purification of the enzyme and the cloning of the cDNA encoding HSL, many research efforts have focused on understanding the activity, regulation, expression and function of this protein. STRUCTURAL AND BIOCHEMICAL PROPERTIES The HSL gene is located on chromosome 19q13.3 (3) and was initially described to contain 9 exons spanning approximately 11 and 10 kB in human (5) and mouse (6), respectively, that encode an mRNA of 2.8 kB (7). Subsequently, two additional exons (termed A and B) that differentially encode 170 and 70 nt 5 untranslated regions were identified approximately 12.5 and 1.5 kB upstream of exon 1, respectively (7). Only the smaller HSL mRNA product is expressed in human adipose tissue. In contrast, five different exons have been reported within 7 kB of the translation start site of exon 1 in mouse HSL, each of which can be alternatively utilized and expressed in mouse adipose tissue to varying degrees (8). In addition to these alternative exons encoding 5 untranslated regions, several isoforms of HSL have been reported. A testis specific exon 15.5 kB upstream of exon 1 of human adipocyte HSL yields a 3.9 kB testicular HSL mRNA and encodes a larger protein (9). A second testis specific exon was identified 12 kB upstream of exon 1 and encodes a protein identical to adipocyte HSL (10). cells may have a specific exon (11) or an alternate translation start site may be 7 kB upstream of exon 1 (8). The purified rat enzyme has a molecular weight of approximately 84,000 Da on SDS-PAGE, corresponding to Abbreviations: ALBP, adipocyte lipid-binding protein; ERK, extracellular signal-regulated kinase; FFA, free fatty acids; HSL, hormonesensitive lipase; PKA, cyclic AMP dependent protein kinase. 1 To whom correspondence should be addressed. e-mail: fbk@stanford.edu DOI 10.1194/jlr.R200009-JLR200 thematic review at P E N N S T A T E U N IV E R S IT Y , on F ebuary 1, 2013 w w w . j.org D ow nladed fom