Branched Fatty Acid Esters of Hydroxy Fatty Acids Are Preferred Substrates of the MODY8 Protein Carboxyl Ester Lipase

Abstract

A recently discovered class of endogenous mammalian lipids, branched fatty acid esters of hydroxy fatty acids (FAHFAs), possess anti-diabetic and anti-inflammatory activities. Here, we identified and validated carboxyl ester lipase (CEL), a pancreatic enzyme hydrolyzing cholesteryl esters and other dietary lipids, as a FAHFA hydrolase. Variants of CEL have been linked to maturity-onset diabetes of the young, type 8 (MODY8) and to chronic pancreatitis. We tested FAHFA hydrolysis activity of the CEL MODY8 variant and found a modest increase in activity as compared with the normal enzyme. Together, the data suggest that CEL might break down dietary FAHFAs.

PAHSAs attenuate immune responses and promote β cell survival in autoimmune diabetic mice

“…Given that FAHFAs are synthesized (25,26) and degraded (58) in mammalian tissues, it is possible that their levels could be increased by targeting biosynthetic or degradative enzymes. The fact that some of the PAHSA hydrolytic enzymes have specific tissue distributions (58,59) may allow targeted increases in PAHSA levels to avoid more systemic immunosuppression.…”

“…Given that FAHFAs are synthesized (25,26) and degraded (58) in mammalian tissues, it is possible that their levels could be increased by targeting biosynthetic or degradative enzymes. The fact that some of the PAHSA hydrolytic enzymes have specific tissue distributions (58,59) may allow targeted increases in PAHSA levels to avoid more systemic immunosuppression. In this context, we recently identified carboxyl ester lipase (CEL) as a FAHFA hydrolase that is highly expressed in pancreatic acinar tissue and hydrolyzes FAHFAs at a much higher rate compared with previously known substrates such as triacylglycerols, diacylglycerols, and cholesteryl esters (58).…”

“…The fact that some of the PAHSA hydrolytic enzymes have specific tissue distributions (58,59) may allow targeted increases in PAHSA levels to avoid more systemic immunosuppression. In this context, we recently identified carboxyl ester lipase (CEL) as a FAHFA hydrolase that is highly expressed in pancreatic acinar tissue and hydrolyzes FAHFAs at a much higher rate compared with previously known substrates such as triacylglycerols, diacylglycerols, and cholesteryl esters (58). CEL appears to be a major PAH-SA hydrolase in the pancreas, since PAHSA hydrolysis was low in pancreatic membranes from CEL-KO mice compared with membranes from WT littermates (58).…”

“…In this context, we recently identified carboxyl ester lipase (CEL) as a FAHFA hydrolase that is highly expressed in pancreatic acinar tissue and hydrolyzes FAHFAs at a much higher rate compared with previously known substrates such as triacylglycerols, diacylglycerols, and cholesteryl esters (58). CEL appears to be a major PAH-SA hydrolase in the pancreas, since PAHSA hydrolysis was low in pancreatic membranes from CEL-KO mice compared with membranes from WT littermates (58). A gain-of-function mutation in CEL causes maturity-onset diabetes of the young type-8, which is characterized by pancreatic islet and acinar dysfunction (60).…”

Branched Fatty Acyl Esters of Hydroxyl Fatty Acids (FAHFAs), Appealing Beneficial Endogenous Fat against Obesity and Type‐2 Diabetes

“…Major FAHFAs are combination of palmitic acid (PA), stearic acid (SA), oleic acid (OA), or palmitoleic acid (PO) with their corresponding hydroxyl fatty acids (HFA: HPA, HAS, HOA, HPO respectively), providing PAHPA, OAHPA, PAHOA, OAHOA, PAHSA and OAHSA (Table 1). [1,2,7] Amongt he observed 16 FAHFAf amilies, Yore et al detected ag reat number of regioisomers. [1] Mass fragmentation allowed the identification of isomersw ith the ester linkagea tp osition C5, C7, C8, C10, C11, C12 and C13.…”