lipolysis

File:Diglyceride Structural Formula V.1.png

File:Monoglyceride Structural Formula V.1.png

In the body, stores of fat are referred to as adipose tissue. In these areas, intracellular triglycerides are stored in cytoplasmic lipid droplets. When lipase enzymes are phosphorylated, they can access lipid droplets and through multiple steps of hydrolysis, breakdown triglycerides into fatty acids and glycerol. Each step of hydrolysis leads to the removal of one fatty acid. The first step and the rate-limiting step of lipolysis is carried out by adipose triglyceride lipase (ATGL). This enzyme catalyzes the hydrolysis of triacylglycerol to diacylglycerol. Subsequently, hormone-sensitive lipase (HSL) catalyzes the hydrolysis of diacylglycerol to monoacylglycerol and monoacylglycerol lipase (MGL) catalyzes the hydrolysis of monoacylglycerol to glycerol.{{cite journal|last1=Frühbeck|first1=G|last2=Méndez-Giménez|first2=L|last3=Fernández-Formoso|first3=JA|last4=Fernández|first4=S|last5=Rodríguez|first5=A|title=Regulation of adipocyte lipolysis.|journal=Nutrition Research Reviews|date=June 2014|volume=27|issue=1|pages=63–93|doi=10.1017/S095442241400002X|pmid=24872083|doi-access=free}}

Perilipin 1A is a key protein regulator of lipolysis in adipose tissue. This lipid droplet-associated protein, when deactivated, will prevent the interaction of lipases with triglycerides in the lipid droplet and grasp the ATGL co-activator, comparative gene identification 58 (CGI-58) (a.k.a. ABHD5). When perilipin 1A is phosphorylated by PKA, it releases CGI-58 and it expedites the docking of phosphorylated lipases to the lipid droplet.{{cite journal|last1=Itabe|first1=H|last2=Yamaguchi|first2=T|last3=Nimura|first3=S|last4=Sasabe|first4=N|title=Perilipins: a diversity of intracellular lipid droplet proteins.|journal=Lipids in Health and Disease|date=28 April 2017|volume=16|issue=1|pages=83|doi=10.1186/s12944-017-0473-y|pmid=28454542|pmc=5410086|doi-access=free}} CGI-58 can be further phosphorylated by PKA to assist in its dispersal to the cytoplasm. In the cytoplasm, CGI-58 can co-activate ATGL.{{cite journal|last1=Sahu-Osen|first1=A|last2=Montero-Moran|first2=G|last3=Schittmayer|first3=M|last4=Fritz|first4=K|last5=Dinh|first5=A|last6=Chang|first6=YF|last7=McMahon|first7=D|last8=Boeszoermenyi|first8=A|last9=Cornaciu|first9=I|last10=Russell|first10=D|last11=Oberer|first11=M|last12=Carman|first12=GM|last13=Birner-Gruenberger|first13=R|last14=Brasaemle|first14=DL|title=CGI-58/ABHD5 is phosphorylated on Ser239 by protein kinase A: control of subcellular localization.|journal=Journal of Lipid Research|date=January 2015|volume=56|issue=1|pages=109–21|doi=10.1194/jlr.M055004 |doi-access=free |pmid=25421061|pmc=4274058}} ATGL activity is also impacted by the negative regulator of lipolysis, G0/G1 switch gene 2 (G0S2). When expressed, G0S2 acts as a competitive inhibitor in the binding of CGI-58.{{cite journal|last1=Cornaciu|first1=I|last2=Boeszoermenyi|first2=A|last3=Lindermuth|first3=H|last4=Nagy|first4=HM|last5=Cerk|first5=IK|last6=Ebner|first6=C|last7=Salzburger|first7=B|last8=Gruber|first8=A|last9=Schweiger|first9=M|last10=Zechner|first10=R|last11=Lass|first11=A|last12=Zimmermann|first12=R|last13=Oberer|first13=M|title=The minimal domain of adipose triglyceride lipase (ATGL) ranges until leucine 254 and can be activated and inhibited by CGI-58 and G0S2, respectively.|journal=PLOS ONE|date=2011|volume=6|issue=10|pages=e26349|doi=10.1371/journal.pone.0026349|pmid=22039468|pmc=3198459|bibcode=2011PLoSO...626349C|doi-access=free}} Fat-specific protein 27 (FSP-27) (a.k.a. CIDEC) is also a negative regulator of lipolysis. FSP-27 expression is negatively correlated with ATGL mRNA levels.{{cite journal|last1=Singh|first1=M|last2=Kaur|first2=R|last3=Lee|first3=MJ|last4=Pickering|first4=RT|last5=Sharma|first5=VM|last6=Puri|first6=V|last7=Kandror|first7=KV|title=Fat-specific protein 27 inhibits lipolysis by facilitating the inhibitory effect of transcription factor Egr1 on transcription of adipose triglyceride lipase.|journal=The Journal of Biological Chemistry|date=23 May 2014|volume=289|issue=21|pages=14481–7|doi=10.1074/jbc.C114.563080|pmid=24742676|pmc=4031504|doi-access=free}}

File:Metabolism1.jpg. Induced by high epinephrine and low insulin levels in the blood, epinephrine binds to beta-adrenergic receptors on the cell membrane of the adipocyte, which causes cAMP to be generated inside the cell.
The cAMP activates protein kinases, which phosphorylate and thus activate hormone-sensitive lipases in the adipocyte.
These lipases cleave free fatty acids from their attachment to glycerol in the lipid droplet of the adipocyte.
The free fatty acids and glycerol are then released into the blood.
The activity of hormone sensitive lipase is regulated by the circulating hormones insulin, glucagon, norepinephrine, and epinephrine. ]]

Lipolysis can be regulated through cAMP's binding and activation of protein kinase A (PKA). PKA can phosphorylate lipases, perilipin 1A, and CGI-58 to increase the rate of lipolysis. Catecholamines bind to 7TM receptors (G protein-coupled receptors) on the adipocyte cell membrane, which activate adenylate cyclase. This results in increased production of cAMP, which activates PKA and leads to an increased rate of lipolysis. Despite glucagon's lipolytic activity (which stimulates PKA as well) in vitro, the role of glucagon in lipolysis in vivo is disputed.{{Cite journal|last1=Schmitz|first1=Ole|last2=Christiansen|first2=Jens Sandahl|last3=Jensen|first3=Michael D.|last4=Møller|first4=Niels|last5=Gravholt|first5=Claus Højbjerg|date=2001-05-01|title=Physiological Levels of Glucagon Do Not Influence Lipolysis in Abdominal Adipose Tissue as Assessed by Microdialysis|journal=The Journal of Clinical Endocrinology & Metabolism|language=en|volume=86|issue=5|pages=2085–2089|doi=10.1210/jcem.86.5.7460|pmid=11344211|issn=0021-972X|doi-access=free}}

Insulin counter-regulates this increase in lipolysis when it binds to insulin receptors on the adipocyte cell membrane. Insulin receptors activate insulin-like receptor substrates. These substrates activate phosphoinositide 3-kinases (PI-3K) which then phosphorylate protein kinase B (PKB) (a.k.a. Akt). PKB subsequently phosphorylates phosphodiesterase 3B (PD3B), which then converts the cAMP produced by adenylate cyclase into 5'AMP. The resulting insulin induced reduction in cAMP levels decreases the lipolysis rate.{{cite journal|last1=Jocken|first1=JW|last2=Blaak|first2=EE|title=Catecholamine-induced lipolysis in adipose tissue and skeletal muscle in obesity.|journal=Physiology & Behavior|date=23 May 2008|volume=94|issue=2|pages=219–30|doi=10.1016/j.physbeh.2008.01.002|pmid=18262211|s2cid=28173901}}

Insulin also acts in the brain at the mediobasal hypothalamus. There, it suppresses lipolysis and decreases sympathetic nervous outflow to the fatty part of the brain matter.{{Cite journal|author1=Scherer T. |author2=O'Hare J. |author3=Diggs-Andrews K. |author4=Schweizer M. |author5=Check B. |author6=Lindner C. |date=1 February 2011|title=Brain Insulin Controls Adipose Tissue Lipolysis and Lipogenesis|url= |journal=Cell Metabolism|volume=13|issue=2|doi=10.1016/j.cmet.2011.01.008|pmid=21284985|pmc=3061443 |display-authors=etal |pages=183–194}} The regulation of this process involves interactions between insulin receptors and gangliosides present in the neuronal cell membrane.{{Cite journal|last1=Herzer|first1=Silke|last2=Meldner|first2=Sascha|last3=Gröne|first3=Hermann-Josef|last4=Nordström|first4=Viola|date=2015-10-01|title=Fasting-Induced Lipolysis and Hypothalamic Insulin Signaling Are Regulated by Neuronal Glucosylceramide Synthase|url=http://diabetes.diabetesjournals.org/content/64/10/3363.full-text.pdf|journal=Diabetes|language=en|volume=64|issue=10|pages=3363–3376|doi=10.2337/db14-1726|issn=0012-1797|pmid=26038579|doi-access=free}}

Triglycerides are transported through the blood to appropriate tissues (adipose, muscle, etc.) by lipoproteins such as Very-Low-Density-Lipoproteins (VLDL). Triglycerides present on the VLDL undergo lipolysis by the cellular lipases of target tissues, which yields glycerol and free fatty acids. Free fatty acids released into the blood are then available for cellular uptake.{{cite web |url=http://themedicalbiochemistrypage.org/fatty-acid-oxidation.html |title=Oxidation of Fatty Acids |access-date=9 April 2012 |first=Michael W |last=King |archive-url=https://web.archive.org/web/20160114211438/http://themedicalbiochemistrypage.org/fatty-acid-oxidation.html |archive-date=14 January 2016 |url-status=dead }}{{self-published source|date=April 2015}}{{self-published inline|date=April 2015}} Free fatty acids not immediately taken up by cells may bind to albumin for transport to surrounding tissues that require energy. Serum albumin is the major carrier of free fatty acids in the blood.Tom Brody, Nutritional Biochemistry, (Academic Press, 2nd edition 1999), 215-216. {{ISBN|0121348369}}

The glycerol also enters the bloodstream and is absorbed by the liver or kidney where it is converted to glycerol 3-phosphate by the enzyme glycerol kinase. Hepatic glycerol 3-phosphate is converted mostly into dihydroxyacetonephosphate (DHAP) and then glyceraldehyde 3-phosphate (GA3P) to rejoin the glycolysis and gluconeogenesis pathway.{{cite book

| last1 = Nelson

| first1 = David L.

| last2 = Cox

| first2 = Michael M.

| date = 2008

| title = Lehninger Principles of Biochemistry

| url = https://books.google.com/books?id=5Ek9J4p3NfkC

| publisher = W. H. Freeman

| page = 650

| isbn = 978-1-4292-2416-1

}}

While lipolysis is triglyceride hydrolysis (the process by which triglycerides are broken down), esterification is the process by which triglycerides are formed. Esterification and lipolysis are, in essence, reversals of one another.{{cite book |author1=Baldwin, Kenneth David Sutherland |author2=Brooks, George H. |author3=Fahey, Thomas D. |title=Exercise physiology: human bioenergetics and its applications |publisher=McGraw-Hill |location=New York |year=2005 |isbn=978-0-07-255642-1 }}{{page needed|date=April 2015}}

Physical lipolysis involves destruction of fat cells containing the fat droplets and can be used as part of cosmetic body contouring procedures. Currently there are four main non-invasive body contouring techniques in aesthetic medicine for reducing localized subcutaneous adipose tissue in addition to the standard minimally invasive liposuction: low-level laser therapy (LLLT), cryolipolysis, radio frequency (RF) and high-intensity focused ultrasound (HIFU).{{cite journal |doi=10.1111/jdv.12994 |pmid=25664493 |title=Non-invasive subcutaneous fat reduction: A review |journal=Journal of the European Academy of Dermatology and Venereology |pages= 1679–88|year=2015 |last1=Kennedy |first1=J. |last2=Verne |first2=S. |last3=Griffith |first3=R. |last4=Falto-Aizpurua |first4=L. |last5=Nouri |first5=K. |volume=29|issue=9 |s2cid=40858507 }}{{cite journal |doi=10.1016/j.cps.2011.05.002 |pmid=21824546 |title=Noninvasive Body Contouring with Radiofrequency, Ultrasound, Cryolipolysis, and Low-Level Laser Therapy |journal=Clinics in Plastic Surgery |volume=38 |issue=3 |pages=503–20, vii–iii |year=2011 |last1=Mulholland |first1=R. Stephen |last2=Paul |first2=Malcolm D. |last3=Chalfoun |first3=Charbel }} However, they are less effective with shorter lasting benefits and can remove significantly smaller amounts of fat compared to traditional surgical liposuction or lipectomy. However, future drug developments can be potentially combined with smaller procedures to augment the result.{{Citation needed|date=January 2021}}

{{reflist}}

• {{MeshName|Lipolysis}}

{{Lipid metabolism}}

{{MetabolismMap}}

{{Use dmy dates|date=May 2019}}

Category:Biochemical reactions

Category:Fatty acids

Category:Hepatology

Category:Lipid methods

Category:Lipid metabolism