Over‐expression of hepatic neutral cytosolic cholesteryl ester hydrolase in mice increases free cholesterol and reduces expression of HMG‐CoAR, CYP27, and CYP7A1

Abstract

Hepatic neutral cytosolic cholesteryl ester hydrolase (hncCEH) is a key enzyme in the regulation of hepatic free cholesterol (FC). In examining the effects of over-expression of this enzyme on cholesterol homeostasis, mice were infected with a recombinant adenovirus construct (AdCEH) of the rat hncCEH cDNA driven by the human cytomegalovirus promoter. Cholesteryl esterase and p-nitrophenylcaprylate (PNPC) esterase activities were measured in liver postmitochondrial supernatants at 1, 3, 7, and 11 d after infection with AdCEH or a control virus expressing beta-galactosidase (AdbetaGAL). The PNPC esterase activity of AdCEH mice peaked threefold higher than controls on day 2, declining on subsequent days. In contrast, cholesteryl esterase peaked eightfold higher than controls on day 3, indicating a shift in substrate selectivity of hncCEH. Hepatic FC peaked at 144% of controls, 7 d postinfection. The mRNAs for cholesterol 7alpha-hydroxylase, sterol 27-hydroxylase, and HMG-CoA reductase decreased to 47, 46, and 58% of controls, respectively, on day 7, coinciding with peak FC concentrations. Coinciding with increased cholesteryl esterase activity, hepatic esterified cholesterol dropped precipitously from day 3 onward, to 11% of controls by day 11. Hepatic TAG levels also declined, consistent with the reported TAG lipase activity of hncCEH. These results demonstrate elevation of FC and depletion of cholesteryl esters by over-expression of hncCEH, which were resistant to compensatory responses by other enzymes of cholesterol homeostasis.

Perilla Oil Supplementation Ameliorates High-Fat/High-Cholesterol Diet Induced Nonalcoholic Fatty Liver Disease in Rats via Enhanced Fecal Cholesterol and Bile Acid Excretion

“…It suggests dietary perilla oil intake contributes to hepatic cholesterol excretion. Several studies have pointed out perilla oil intake leads to increase of bile acid excretion via upregulating the expression of CYP7A1 and CYP27A1, two key enzymes in charge of bile acid production [31]. In the present study, the expressions of Cyp7a1 and Cyp27a1 were reduced in HFD group and increased in POH group (Figure 9); it demonstrates that the cholesterol-lowering effects of perilla oil partly are attributed to the elevated bile acid excretion.…”

“…The major sources of hepatic cholesterol are uptake from plasma lipoprotein and de novo synthesis. The 3-hydroxy-3-methylglutaryl-coenzyme reductase (HMGCoAR) is the key rate-limiting enzyme in cholesterol synthesis [31]. HFD intake decreased its expression in liver, and the expressions of other enzymes in charge of cholesterol synthesis such as phosphomevalonate kinase and farnesyl diphosphate synthase were also decreased.…”

Disturbed cholesterol homeostasis in hormone-sensitive lipase-null mice

“…Whether HSL is expressed and enzymatically active in the liver has been debated. The data presented here suggest that HSL indeed functions as a cytosolic cholesterol ester hydrolase in the liver, although its importance in relation to the other described neutral cytosolic cholesterol ester hydrolase remains to be clarified (21,50).…”

Fish oil alleviated high-fat diet–induced non-alcoholic fatty liver disease via regulating hepatic lipids metabolism and metaflammation: a transcriptomic study

“…In the transcriptomic results, a series of DEGs between CON vs. WD or FOH vs. WD group were enriched in cholesterol metabolism pathways. Though both high caloric diets intake decreased the expression of key rate-limiting enzyme in cholesterol synthesis: 3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMGCoAR) in the liver, fish oil consumption regulated the hepatic expression of a serial of genes related to cholesterol transport, including: Fat/CD36 , Lox1 and Scarb1 [ 27 , 28 ], which were associated with cholesterol uptake; Abcg5/8 , which were involved in cholesterol excretion [ 29 ]; and Cyp7a1 and Cyp27a1 , which were connected to bile acid excretion [ 30 ].…”