PMC:3220857 / 13144-20597 JSONTXT

{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/3220857","sourcedb":"PMC","sourceid":"3220857","source_url":"https://www.ncbi.nlm.nih.gov/pmc/3220857","text":"CONCLUSIONS\nA main finding from the current study is that prolonged caloric restriction by a 16-week VLCD in obese patients with type 2 diabetes mellitus and hepatic steatosis, which considerably reduces hepatic TG content (−85%) (11), also markedly decreases plasma CETP concentration (−18.2%). This observation corroborates our recent finding that a reduction of the hepatic lipid content (−30.5%), as induced by pioglitazone, also associates with a reduction in plasma CETP concentration (−11.6%) in patients with type 2 diabetes mellitus (10). However, the potency of prolonged caloric restriction to reduce hepatic lipid content and plasma CETP concentration exceeds that of pioglitazone treatment considerably.\nThese data are in full accordance with our previous observations that lowering hepatic lipids (i.e., TG as well as cholesterol) in APOE*3-Leiden.CETP mice by classical lipid-lowering drugs decreased hepatic CETP mRNA expression, resulting in decreased plasma CETP concentration (6–8). Because CETP expression is regulated by liver X receptor α (LXRα) for which oxysterols are natural ligands (12) and the liver cholesterol level determines LXRα activation (13), we concluded from those studies that a decrease in hepatic cholesterol content, associated with a decrease in cholesterol derivatives, reduces hepatic LXRα activation, thereby downregulating CETP mRNA transcription. Although it is unknown whether hepatic TG levels reflect levels of hepatic cholesterol and oxysterols in the current study, since we cannot assess hepatic (oxy)sterols noninvasively in humans, hepatic TG and cholesterol levels were highly correlated (r = 0.867) in 33 Chinese subjects (Dr. P. Parini, personal communication). Therefore, it is likely that the reduction in plasma CETP concentration induced by VLCD also reduces hepatic LXRα-activated CETP mRNA transcription, thereby reducing plasma CETP. Our data corroborate those of Laimer et al. (14) who showed that substantial weight loss in morbidly obese women induced by laparoscopic gastric banding surgery also decreased plasma CETP mass (−8.3%) at 1 year after surgery.\nThe effect of caloric restriction on HDL levels is still under debate. Although a single study reported that an average of 6 years of caloric restriction in 18 subjects increased HDL-cholesterol (15), other studies demonstrated that both 6 months and 2 years of caloric restriction in eight subjects in fact decreased plasma HDL-cholesterol (16,17). Moreover, caloric restriction had conflicting effects on HDL-cholesterol among different diet groups even in one study: HDL-cholesterol was either increased or unaffected (18). The current study is the first to show that caloric restriction by a VLCD increased the plasma level of the main HDL protein constituent apoAI (+16.2%), which is supposed to be a good (negative) predictor of cardiovascular disease risk (19). However, the VLCD did not increase HDL-cholesterol levels. Our previous studies in mice (6–8) and in patients with type 2 diabetes mellitus (10) showed that reduction of hepatic lipids and plasma CETP, as induced by drugs, were in fact related to increased plasma HDL-cholesterol levels. In fact, treatment of only 20 patients with type 2 diabetes mellitus with pioglitazone resulted in a significant increase in HDL-cholesterol despite less pronounced decreases in hepatic lipid and plasma CETP (10), suggesting that our present study including 27 patients would not be underpowered to detect a potential effect on HDL-cholesterol. It is known that the LXRα target ATP binding cassette A1 (ABCA1) plays a crucial role in HDL maturation by mediating the lipidation of plasma apoAI (20). Furthermore, hepatic ABCA1 is the main contributor to the loading of HDL with cholesterol as evidenced by studies in mice that selectively lack ABCA1 from the liver (21). Collectively, it is thus conceivable that the dramatic reduction in hepatic lipids largely downregulates the hepatic expression of ABCA1, resulting in reduced lipidation of plasma apoAI with liver-derived cholesterol, thereby counteracting the expected rise in HDL-cholesterol as a result of the reduction in CETP.\nThe reduced ratio of HDL-cholesterol over apoAI as induced by VLCD may be expected to result in an increased ability of total plasma and apoB-depleted plasma to induce cholesterol efflux from cholesterol-laden macrophages. However, we observed that the VLCD actually reduced the capacity of total plasma and apoB-depleted plasma to induce cholesterol efflux from THP-1 cells, even after discarding the three subjects showing the largest decrease in cholesterol efflux from the analysis. Correlation analysis revealed that HDL constituents (cholesterol, phospholipid, and apoAI) did not correlate with cholesterol efflux to plasma. Instead, the decrease in cholesterol efflux to plasma was mainly related to the decrease in total phospholipid levels in plasma. Collectively, these data indicate that the total lipoprotein surface area in plasma, rather than the HDL level, determines the capacity of plasma to induce cholesterol efflux.\nOur findings are in line with those of a recent study showing that the cholesterol efflux capacity of plasma was independent of total HDL-cholesterol or apoAI levels (22). In fact, independently of HDL-cholesterol, sera with high efflux capacity had a significant increase in ABCA1-mediated efflux as a result of the presence of preβ-1 HDL. Likewise, another study showed that, although both pioglitazone and statins increase HDL-cholesterol, pioglitazone but not statins increases the cholesterol efflux capacity of plasma, and no correlation was noted between the change in HDL-cholesterol and the change in cholesterol efflux capacity (23). Overall, the cholesterol efflux capacity of plasma is thus not simply related to HDL-cholesterol or apoAI, although the capacity of HDL to mediate cholesterol efflux from macrophages has recently been established to strongly inversely associate with carotid intima-media thickness and likelihood of angiographic coronary artery disease (23). The fact that we were unable to detect a correlation between cholesterol efflux and HDL-cholesterol or apoAI thus probably indicates that VLCD does not improve the functionality of HDL with respect to mediating cholesterol efflux.\nA limitation of the current study may be the small study group. Although we initially included 27 patients for the VLCD intervention, hepatic TG quantification by MRS was possible in only 12 patients, mainly related to limitations for maximum weight and circumference of the MRI scanner. Second, the design of the current human study does not permit to assess causal relationships between hepatic lipid content and plasma CETP or apoAI level. Nonetheless, the results are in accordance with data obtained from mechanistic studies in a mouse model relevant for human lipoprotein metabolism (6–8).\nIn conclusion, this study indicates that prolonged caloric restriction, which considerably reduces hepatic TG content, also markedly decreases plasma CETP concentration. This is in full accordance with our previous findings in APOE*3-Leiden.CETP mice, in which we showed that classical lipid-lowering drugs concurrently lowered hepatic lipids resulting in decreased plasma CETP concentration. Furthermore, the VLCD increased plasma apoAI levels without improving functionality of HDL with respect to cholesterol efflux from macrophages.","divisions":[{"label":"title","span":{"begin":0,"end":11}},{"label":"p","span":{"begin":12,"end":716}},{"label":"p","span":{"begin":717,"end":2125}},{"label":"p","span":{"begin":2126,"end":4167}},{"label":"p","span":{"begin":4168,"end":5103}},{"label":"p","span":{"begin":5104,"end":6320}},{"label":"p","span":{"begin":6321,"end":6916}}],"tracks":[{"project":"2_test","denotations":[{"id":"21994427-18786482-25127316","span":{"begin":231,"end":233},"obj":"18786482"},{"id":"21994427-20150294-25127317","span":{"begin":543,"end":545},"obj":"20150294"},{"id":"21994427-17868678-25127318","span":{"begin":996,"end":997},"obj":"17868678"},{"id":"21994427-17525476-25127318","span":{"begin":996,"end":997},"obj":"17525476"},{"id":"21994427-18669886-25127318","span":{"begin":996,"end":997},"obj":"18669886"},{"id":"21994427-10683381-25127319","span":{"begin":1110,"end":1112},"obj":"10683381"},{"id":"21994427-1401066-25127320","span":{"begin":1174,"end":1176},"obj":"1401066"},{"id":"21994427-19789902-25127321","span":{"begin":1945,"end":1947},"obj":"19789902"},{"id":"21994427-15096581-25127322","span":{"begin":2322,"end":2324},"obj":"15096581"},{"id":"21994427-9570177-25127323","span":{"begin":2468,"end":2470},"obj":"9570177"},{"id":"21994427-1454844-25127324","span":{"begin":2471,"end":2473},"obj":"1454844"},{"id":"21994427-19570664-25127325","span":{"begin":2648,"end":2650},"obj":"19570664"},{"id":"21994427-11755609-25127326","span":{"begin":2890,"end":2892},"obj":"11755609"},{"id":"21994427-17868678-25127327","span":{"begin":2984,"end":2985},"obj":"17868678"},{"id":"21994427-17525476-25127327","span":{"begin":2984,"end":2985},"obj":"17525476"},{"id":"21994427-18669886-25127327","span":{"begin":2984,"end":2985},"obj":"18669886"},{"id":"21994427-20150294-25127328","span":{"begin":3036,"end":3038},"obj":"20150294"},{"id":"21994427-20150294-25127329","span":{"begin":3392,"end":3394},"obj":"20150294"},{"id":"21994427-10918065-25127330","span":{"begin":3677,"end":3679},"obj":"10918065"},{"id":"21994427-15841208-25127331","span":{"begin":3848,"end":3850},"obj":"15841208"},{"id":"21994427-20075420-25127332","span":{"begin":5271,"end":5273},"obj":"20075420"},{"id":"21994427-21226578-25127333","span":{"begin":5743,"end":5745},"obj":"21226578"},{"id":"21994427-21226578-25127334","span":{"begin":6085,"end":6087},"obj":"21226578"},{"id":"21994427-17868678-25127335","span":{"begin":6911,"end":6912},"obj":"17868678"},{"id":"21994427-17525476-25127335","span":{"begin":6911,"end":6912},"obj":"17525476"},{"id":"21994427-18669886-25127335","span":{"begin":6911,"end":6912},"obj":"18669886"}],"attributes":[{"subj":"21994427-18786482-25127316","pred":"source","obj":"2_test"},{"subj":"21994427-20150294-25127317","pred":"source","obj":"2_test"},{"subj":"21994427-17868678-25127318","pred":"source","obj":"2_test"},{"subj":"21994427-17525476-25127318","pred":"source","obj":"2_test"},{"subj":"21994427-18669886-25127318","pred":"source","obj":"2_test"},{"subj":"21994427-10683381-25127319","pred":"source","obj":"2_test"},{"subj":"21994427-1401066-25127320","pred":"source","obj":"2_test"},{"subj":"21994427-19789902-25127321","pred":"source","obj":"2_test"},{"subj":"21994427-15096581-25127322","pred":"source","obj":"2_test"},{"subj":"21994427-9570177-25127323","pred":"source","obj":"2_test"},{"subj":"21994427-1454844-25127324","pred":"source","obj":"2_test"},{"subj":"21994427-19570664-25127325","pred":"source","obj":"2_test"},{"subj":"21994427-11755609-25127326","pred":"source","obj":"2_test"},{"subj":"21994427-17868678-25127327","pred":"source","obj":"2_test"},{"subj":"21994427-17525476-25127327","pred":"source","obj":"2_test"},{"subj":"21994427-18669886-25127327","pred":"source","obj":"2_test"},{"subj":"21994427-20150294-25127328","pred":"source","obj":"2_test"},{"subj":"21994427-20150294-25127329","pred":"source","obj":"2_test"},{"subj":"21994427-10918065-25127330","pred":"source","obj":"2_test"},{"subj":"21994427-15841208-25127331","pred":"source","obj":"2_test"},{"subj":"21994427-20075420-25127332","pred":"source","obj":"2_test"},{"subj":"21994427-21226578-25127333","pred":"source","obj":"2_test"},{"subj":"21994427-21226578-25127334","pred":"source","obj":"2_test"},{"subj":"21994427-17868678-25127335","pred":"source","obj":"2_test"},{"subj":"21994427-17525476-25127335","pred":"source","obj":"2_test"},{"subj":"21994427-18669886-25127335","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#93eca6","default":true}]}]}}