Hormone-Sensitive Lipase Deficiency in Humans
Authors: Rudolf Zechner, Dominique Langin
Journal: Cell Metabolism (2014)

The breakdown of cellular fat stores fuels energy production and multiple anabolic processes. Albert et al., 2014Albert J.S. Yerges-Armstrong L.M. Horenstein R.B. Pollin T.I. Sreenivasan U.T. Chai S. Blaner W.S. Snitker S. O'Connell J.R. Gong D.W. et al.N. Engl. J. Med. 2014; 370: 2307-2315Crossref PubMed Scopus (131) Google Scholar demonstrate that the lack of hormone-sensitive lipase, a member of the enzyme trio that catabolizes fat, has pronounced effects on lipid metabolism, glucose homeostasis, and cell signaling in humans. The breakdown of cellular fat stores fuels energy production and multiple anabolic processes. Albert et al., 2014Albert J.S. Yerges-Armstrong L.M. Horenstein R.B. Pollin T.I. Sreenivasan U.T. Chai S. Blaner W.S. Snitker S. O'Connell J.R. Gong D.W. et al.N. Engl. J. Med. 2014; 370: 2307-2315Crossref PubMed Scopus (131) Google Scholar demonstrate that the lack of hormone-sensitive lipase, a member of the enzyme trio that catabolizes fat, has pronounced effects on lipid metabolism, glucose homeostasis, and cell signaling in humans. Adipose tissue is the body's largest reservoir of energy and a major source of metabolic fuel. In periods of food supply, excess nutrients are stored as triglycerides (TGs) in white adipose tissue, whereas during energy demand, TGs are hydrolyzed to release nonesterified fatty acids (FAs) into the bloodstream. Nonadipose tissues, in turn, utilize FAs effectively for energy production, membrane lipid synthesis, or lipid signaling. The transient storage of FAs as TGs in adipose tissue is also important to protect the organism from harmful "lipotoxic" effects of excessive intracellular FA concentrations including ectopic lipid deposition in liver and skeletal muscle and the development of insulin resistance. Thus, alterations in adipose tissue TG metabolism have profound effects on whole-body homeostasis. The catabolic pathway hydrolyzing TGs is called lipolysis. It is an exquisitely controlled process involving a variety of cell-surface receptors, neurotransmitters, hormones, and paracrine factors that result in the sequential enzymatic hydrolysis of three FA-glycerol ester bonds (Lafontan and Langin, 2009Lafontan M. Langin D. Prog. Lipid Res. 2009; 48: 275-297Crossref PubMed Scopus (545) Google Scholar, Zechner et al., 2012Zechner R. Zimmermann R. Eichmann T.O. Kohlwein S.D. Haemmerle G. Lass A. Madeo F. Cell Metab. 2012; 15: 279-291Abstract Full Text Full Text PDF PubMed Scopus (695) Google Scholar). The major enzymes working in a step-wise fashion are adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase (MGL). Mouse and human studies identified ATGL as the major TG lipase, while HSL and MGL predominantly hydrolyze diglycerides (DGs) and monoglycerides (MGs), respectively. HSL has a broader substrate specificity than the other enzymes additionally hydrolyzing TGs, MGs, retinyl esters (REs), and cholesterol esters (CEs). The phenotypes observed in lipase-deficient mouse models are consistent with these enzymatic activities. ATGL-deficient mice accumulate TGs in multiple tissues with the highest fat content in oxidative tissues such as brown adipose tissue, cardiac muscle, and kidney. Loss of ATGL in cardiac muscle results in severe cardiomyopathy, heart failure, and premature death in ATGL knockout mice at the age of 4 months. In humans, ATGL deficiency causes neutral lipid storage disease with myopathy (NLSDM) (Fischer et al., 2007Fischer J. Lefèvre C. Morava E. Mussini J.M. Laforêt P. Negre-Salvayre A. Lathrop M. Salvayre R. Nat. Genet. 2007; 39: 28-30Crossref PubMed Scopus (366) Google Scholar), a condition similar to the knockout phenotypes observed in mice. Clinical manifestations start later and are more variable in humans than in mice, but many patients also develop a severe cardiomyopathy requiring heart transplantation to prevent cardiac death. Despite a very detailed knowledge of the biochemical and physiological functions of HSL, a clear link between HSL deficiency and human disease was missing. Now, Albert et al., 2014Albert J.S. Yerges-Armstrong L.M. Horenstein R.B. Pollin T.I. Sreenivasan U.T. Chai S. Blaner W.S. Snitker S. O'Connell J.R. Gong D.W. et al.N. Engl. J. Med. 2014; 370: 2307-2315Crossref PubMed Scopus (131) Google Scholar report in the June 12 issue of the New England Journal of Medicine the first clinical characterization of individuals with a frameshift mutation in the LIPE gene encoding HSL (Albert et al., 2014Albert J.S. Yerges-Armstrong L.M. Horenstein R.B. Pollin T.I. Sreenivasan U.T. Chai S. Blaner W.S. Snitker S. O'Connell J.R. Gong D.W. et al.N. Engl. J. Med. 2014; 370: 2307-2315Crossref PubMed Scopus (131) Google Scholar). A 19 bp deletion in the last exon results in the addition of 86 amino acids to the C terminus of the protein. The mutation leads to lower abundance of HSL protein in adipose tissue of carriers (−50% in heterozygotes, −100% in homozygotes) due to either decreased enzyme synthesis or increased turnover. Subcutaneous adipose tissue from a homozygous carrier exhibited drastically decreased basal and stimulated glycerol release consistent with a defect in TG catabolism to FAs and glycerol. The clinical manifestations associated with defective HSL expression in carriers are less pronounced than in NLSDM and resemble in some but not all aspects the phenotype observed in HSL-deficient mice (Osuga et al., 2000Osuga J. Ishibashi S. Oka T. Yagyu H. Tozawa R. Fujimoto A. Shionoiri F. Yahagi N. Kraemer F.B. Tsutsumi O. Yamada N. Proc. Natl. Acad. Sci. USA. 2000; 97: 787-792Crossref PubMed Scopus (502) Google Scholar). Both humans and mice are not obese and develop partial lipodystrophies with age. Reduced peroxisome proliferator-activated receptor (PPAR)-γ signaling in adipose tissue leads to decreased adipogenesis, lipogenesis, and lipid synthesis. These findings by Albert and colleagues are important because they provide compelling evidence for an essential involvement of HSL-mediated lipolysis in cellular signaling processes also in humans. The data support earlier proposals from mouse studies that the HSL reaction provides ligands to activate the central adipogenesis transcription factors PPARγ and/or retinoid-X receptor (RXR)-α (Strom et al., 2009Strom K. Gundersen T.E. Hansson O. Lucas S. Fernandez C. Blomhoff R. Holm C. FASEB. 2009; 23: 2307-2316Crossref PubMed Scopus (69) Google Scholar, Zimmermann et al., 2003Zimmermann R. Haemmerle G. Wagner E.M. Strauss J.G. Kratky D. Zechner R. J. Lipid Res. 2003; 44: 2089-2099Crossref PubMed Scopus (93) Google Scholar). Together with the recent finding that ATGL-mediated lipolysis is essential for PPARα signaling in cardiac muscle (Haemmerle et al., 2011Haemmerle G. Moustafa T. Woelkart G. Büttner S. Schmidt A. van de Weijer T. Hesselink M. Jaeger D. Kienesberger P.C. Zierler K. et al.Nat. Med. 2011; 17: 1076-1085Crossref PubMed Scopus (500) Google Scholar), these data underline the general importance of lipolysis for the regulation of gene transcription by nuclear receptors. Interestingly, the impairment of adipogenesis in humans with the HSL mutation exhibits site specificity; certain fat depots are affected (e.g., subcutaneous fat in different locations), while others are not (e.g., visceral fat). In addition to common findings in mice and humans with defects in HSL-mediated lipolysis, several notable differences were also observed. (1) Unlike male HSL-deficient mice, a male homozygous carrier of the HSL mutation has offspring. The mechanisms underlying these differences in fertility are unknown but may imply species-specific differences in the role of HSL in spermatogenesis. (2) Despite decreased lipolytic rates, homozygous carriers have increased liver fat, increased plasma TG concentrations, and decreased plasma HDL. This is in sharp contrast to the phenotype described for HSL-deficient mice, where the lipolytic defect leads to reduced FA transport to the liver, decreased liver fat, decreased VLDL synthesis, lower plasma TG, and increased plasma HDL. The differences may be explained by the fact that lipid and lipoprotein parameters were analyzed at an age when the adipose tissue of human HSL mutation carriers already exhibited diminished lipid storage capacity (due to decreased PPARγ signaling), leading to ectopic fat accumulation and hepatosteatosis (Figure 1). In contrast, HSL-knockout mice were analyzed at a younger age when the fat storage function of white adipose tissue was relatively normal and ectopic lipid accumulation did not occur. Other explanations include the possibility that hepatic HSL affects lipid and lipoprotein metabolism differently in humans and mice. (3) The most noticeable differences between humans and mice with defective HSL were observed with regard to glucose metabolism. In contrast to HSL-deficient mice, which are nondiabetic, all four homozygous carriers investigated by Albert et al. developed diabetes. The authors convincingly reason that the partial lipodystrophy in these patients may lead to insulin resistance and type 2 diabetes. However, the small number of affected patients and a potential impact of environmental/behavioral effects in these individuals require confirmation of a role of HSL the pathogenesis of diabetes in a larger study group. The interpretation of the phenotype of heterozygous carriers is more challenging. Compared to noncarriers, these individuals show very modest changes in blood lipid profiles and fasting plasma glucose concentrations but display a marked decrease in glucose tolerance and a higher risk of type 2 diabetes. This is the opposite finding to what was reported for haploinsufficient mice with only one intact allele of Lipe and a comparable decrease in HSL protein abundance in adipose tissue (∼50%) (Girousse et al., 2013Girousse A. Tavernier G. Valle C. Moro C. Mejhert N. Dinel A.L. Houssier M. Roussel B. Besse-Patin A. Combes M. et al.PLoS Biol. 2013; 11: e1001485Crossref PubMed Scopus (149) Google Scholar). These mice exhibit improved tissue and whole-body insulin sensitivity and increased glucose tolerance. Similarly, chronic treatment of wild-type mice with an HSL inhibitor improved insulin sensitivity in mice. Also in humans, a negative relationship between fat cell lipolysis and insulin sensitivity has been reported (Arner and Langin, 2014Arner P. Langin D. Trends Endocrinol. Metab. 2014; 25: 255-262Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, Girousse et al., 2013Girousse A. Tavernier G. Valle C. Moro C. Mejhert N. Dinel A.L. Houssier M. Roussel B. Besse-Patin A. Combes M. et al.PLoS Biol. 2013; 11: e1001485Crossref PubMed Scopus (149) Google Scholar). How can these results be reconciled with decreased insulin sensitivity in heterozygous carriers of the frameshift mutation in the human LIPE gene? Unlike haploinsufficient mice, heterozygous carriers show intact adipocyte lipolysis and no evidence for an accumulation of the major HSL substrates (DGs, CEs, and REs) in adipose tissue. Therefore, it is conceivable that the presence of the enzymatically inactive mutant protein provokes metabolic effects by unknown mechanisms that differ from those observed in mice with defective lipolysis. Taken together, the work by Albert et al. underlines the key role of HSL for lipid metabolism, energy homeostasis, and cell signaling in humans. Important questions, however, remain open: Which lipolytic mediators are involved in the regulation of gene transcription by nuclear receptors? What are the (species-specific) mechanistic links between HSL deficiency insulin resistance and diabetes? What is the molecular basis for hepatosteatosis and dyslipidemia in humans lacking HSL? Additional studies in humans and mice with HSL deficiency will answer these questions. R. Z. is supported by the Fondation Leducq (12CVD04), an ERC-Advanced grant (LIPO.ChEX Nr. 340896), the Z136 Wittgenstein Award, and the F30 SFB LIPOTOX from the Austrian Science Fund. D. L. is funded by Inserm, Université Paul Sabatier, Institut Universitaire de France, Agence Nationale de la Recherche, Région Midi-Pyrénées, and the European Commission framework program DIABAT.