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Article ; Online: Triglycerides in Nonalcoholic Fatty Liver Disease: Guilty Until Proven Innocent.

Semova, Ivana / Biddinger, Sudha B

2021 Volume 42, Issue 3, Page(s) 183–190

Abstract: End-stage liver disease (ESLD) is a rare but often fatal complication of nonalcoholic fatty liver disease (NAFLD). In NAFLD, insulin resistance, which is clinically defined as the impairment of insulin's ability to maintain glucose homeostasis, is ... ...

Abstract	End-stage liver disease (ESLD) is a rare but often fatal complication of nonalcoholic fatty liver disease (NAFLD). In NAFLD, insulin resistance, which is clinically defined as the impairment of insulin's ability to maintain glucose homeostasis, is associated with perturbations in insulin action that promote triglyceride accumulation, such as increasing de novo lipogenesis. However, the key step in the development of ESLD is not the accumulation of triglycerides, but hepatocyte injury. Whether and how triglycerides promote hepatocyte injury remains unclear. Consequently, it is difficult to predict whether drugs designed to reduce hepatic triglycerides will prevent the most important complications of NAFLD.
MeSH term(s)	Humans ; Insulin Resistance ; Lipogenesis ; Liver/metabolism ; Non-alcoholic Fatty Liver Disease/drug therapy ; Non-alcoholic Fatty Liver Disease/metabolism ; Triglycerides/metabolism
Chemical Substances	Triglycerides
Language	English
Publishing date	2021-01-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	282846-7
ISSN	1873-3735 ; 0165-6147
ISSN (online)	1873-3735
ISSN	0165-6147
DOI	10.1016/j.tips.2020.12.001
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Zs.A 1513: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 6: Show issues

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Article ; Online: Evaluating human genetic support for hypothesized metabolic disease genes.

Dornbos, Peter / Singh, Preeti / Jang, Dong-Keun / Mahajan, Anubha / Biddinger, Sudha B / Rotter, Jerome I / McCarthy, Mark I / Flannick, Jason

Cell metabolism

2022 Volume 34, Issue 5, Page(s) 661–666

Abstract: We investigate the extent to which human genetic data are incorporated into studies that hypothesize novel links between genes and metabolic disease. To lower the barriers to using genetic data, we present an approach to enable researchers to evaluate ... ...

Abstract	We investigate the extent to which human genetic data are incorporated into studies that hypothesize novel links between genes and metabolic disease. To lower the barriers to using genetic data, we present an approach to enable researchers to evaluate human genetic support for experimentally determined hypotheses.
MeSH term(s)	Human Genetics ; Humans ; Metabolic Diseases/genetics
Language	English
Publishing date	2022-04-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2022.03.011
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Zs.A 6169: Show issues

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Article ; Online: Inhibition of nonalcoholic fatty liver disease in mice by selective inhibition of mTORC1.

Gosis, Bridget S / Wada, Shogo / Thorsheim, Chelsea / Li, Kristina / Jung, Sunhee / Rhoades, Joshua H / Yang, Yifan / Brandimarto, Jeffrey / Li, Li / Uehara, Kahealani / Jang, Cholsoon / Lanza, Matthew / Sanford, Nathan B / Bornstein, Marc R / Jeong, Sunhye / Titchenell, Paul M / Biddinger, Sudha B / Arany, Zoltan

Science (New York, N.Y.)

2022 Volume 376, Issue 6590, Page(s) eabf8271

Abstract: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) remain without effective therapies. The mechanistic target of rapamycin complex 1 (mTORC1) pathway is a potential therapeutic target, but conflicting interpretations have ... ...

Abstract	Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) remain without effective therapies. The mechanistic target of rapamycin complex 1 (mTORC1) pathway is a potential therapeutic target, but conflicting interpretations have been proposed for how mTORC1 controls lipid homeostasis. We show that selective inhibition of mTORC1 signaling in mice, through deletion of the RagC/D guanosine triphosphatase-activating protein folliculin (FLCN), promotes activation of transcription factor E3 (TFE3) in the liver without affecting other mTORC1 targets and protects against NAFLD and NASH. Disease protection is mediated by TFE3, which both induces lipid consumption and suppresses anabolic lipogenesis. TFE3 inhibits lipogenesis by suppressing proteolytic processing and activation of sterol regulatory element-binding protein-1c (SREBP-1c) and by interacting with SREBP-1c on chromatin. Our data reconcile previously conflicting studies and identify selective inhibition of mTORC1 as a potential approach to treat NASH and NAFLD.
MeSH term(s)	Animals ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics ; Gene Deletion ; Liver/metabolism ; Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mice ; Non-alcoholic Fatty Liver Disease/therapy ; Sterol Regulatory Element Binding Protein 1/genetics ; Sterol Regulatory Element Binding Protein 1/metabolism
Chemical Substances	Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; Sterol Regulatory Element Binding Protein 1 ; Tcfe3 protein, mouse (136896-33-8) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1)
Language	English
Publishing date	2022-04-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.abf8271
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Zs.A 27: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 77: Show issues

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Article ; Online: The regulation of ApoB metabolism by insulin.

Haas, Mary E / Attie, Alan D / Biddinger, Sudha B

Trends in endocrinology and metabolism: TEM

2013 Volume 24, Issue 8, Page(s) 391–397

Abstract: The leading cause of death in diabetic patients is cardiovascular disease. Apolipoprotein B (ApoB ...

Abstract	The leading cause of death in diabetic patients is cardiovascular disease. Apolipoprotein B (ApoB)-containing lipoprotein particles, which are secreted and cleared by the liver, are essential for the development of atherosclerosis. Insulin plays a key role in the regulation of ApoB. Insulin decreases ApoB secretion by promoting ApoB degradation in the hepatocyte. In parallel, insulin promotes clearance of circulating ApoB particles by the liver via the low-density lipoprotein receptor (LDLR), LDLR-related protein 1 (LRP1), and heparan sulfate proteoglycans (HSPGs). Consequently, the insulin-resistant state of type 2 diabetes (T2D) is associated with increased secretion and decreased clearance of ApoB. Here, we review the mechanisms by which insulin controls the secretion and uptake of ApoB in normal and diabetic livers.
MeSH term(s)	Animals ; Apolipoproteins B/metabolism ; Cardiovascular Diseases/metabolism ; Humans ; Insulin/metabolism ; Insulin Resistance/physiology ; Lipoproteins, VLDL/metabolism
Chemical Substances	Apolipoproteins B ; Insulin ; Lipoproteins, VLDL
Language	English
Publishing date	2013-05-27
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1042384-9
ISSN	1879-3061 ; 1043-2760
ISSN (online)	1879-3061
ISSN	1043-2760
DOI	10.1016/j.tem.2013.04.001
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Zs.A 2999: Show issues

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Article ; Online: Dissecting the role of insulin resistance in the metabolic syndrome.

Haas, Joel T / Biddinger, Sudha B

Current opinion in lipidology

2009 Volume 20, Issue 3, Page(s) 206–210

Abstract: ... can produce hyperglycemia, increased apolipoprotein B secretion and atherosclerosis, and increased biliary ...

Abstract	Purpose of review: Over 20 years ago, insulin resistance was postulated to play a central role in the pathogenesis of the metabolic syndrome. However, this has been difficult to prove, leading to a great deal of controversy within the field. Recent studies on mice and humans with genetic defects in insulin signaling have allowed us, for the first time, to dissect which features of the metabolic syndrome can be caused by insulin resistance. Recent findings: Liver insulin receptor knockout mice show that hepatic insulin resistance can produce hyperglycemia, increased apolipoprotein B secretion and atherosclerosis, and increased biliary cholesterol secretion and cholesterol gallstones. Many of these changes may be due to disinhibition of the transcription factor, forkhead box O1. Yet, neither liver insulin receptor knockout mice nor humans with insulin receptor mutations develop the hypertriglyceridemia or hepatic steatosis associated with the metabolic syndrome. Summary: These data point to a central role for insulin resistance in the pathogenesis of the metabolic syndrome, as hyperglycemia, atherosclerosis, and cholesterol gallstones can all be caused by insulin resistance. However, hypertriglyceridemia and hepatic steatosis are not due directly to insulin resistance and should be considered pathogenically distinct features of the metabolic syndrome.
MeSH term(s)	Animals ; Humans ; Insulin/metabolism ; Metabolic Syndrome/metabolism ; Signal Transduction
Chemical Substances	Insulin
Language	English
Publishing date	2009-10-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1045394-5
ISSN	1473-6535 ; 0957-9672
ISSN (online)	1473-6535
ISSN	0957-9672
DOI	10.1097/MOL.0b013e32832b2024
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Zs.A 3010: Show issues

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Article ; Online: Insulin Prevents Hypercholesterolemia by Suppressing 12α-Hydroxylated Bile Acids.

Semova, Ivana / Levenson, Amy E / Krawczyk, Joanna / Bullock, Kevin / Gearing, Mary E / Ling, Alisha V / Williams, Kathryn A / Miao, Ji / Adamson, Stuart S / Shin, Dong-Ju / Chahar, Satyapal / Graham, Mark J / Crooke, Rosanne M / Hagey, Lee R / Vicent, David / de Ferranti, Sarah D / Kidambi, Srividya / Clish, Clary B / Biddinger, Sudha B

Circulation

2022 Volume 145, Issue 13, Page(s) 969–982

Abstract: Background: The risk of cardiovascular disease in type 1 diabetes remains extremely high, despite marked advances in blood glucose control and even the widespread use of cholesterol synthesis inhibitors. Thus, a deeper understanding of insulin ... ...

Abstract	Background: The risk of cardiovascular disease in type 1 diabetes remains extremely high, despite marked advances in blood glucose control and even the widespread use of cholesterol synthesis inhibitors. Thus, a deeper understanding of insulin regulation of cholesterol metabolism, and its disruption in type 1 diabetes, could reveal better treatment strategies. Methods: To define the mechanisms by which insulin controls plasma cholesterol levels, we knocked down the insulin receptor, FoxO1, and the key bile acid synthesis enzyme, CYP8B1. We measured bile acid composition, cholesterol absorption, and plasma cholesterol. In parallel, we measured markers of cholesterol absorption and synthesis in humans with type 1 diabetes treated with ezetimibe and simvastatin in a double-blind crossover study. Results: Mice with hepatic deletion of the insulin receptor showed marked increases in 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol. This phenotype was entirely reversed by hepatic deletion of Conclusions: Insulin, by inhibiting FoxO1 in the liver, reduces 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol levels. Thus, type 1 diabetes leads to a unique set of derangements in cholesterol metabolism, with increased absorption rather than synthesis. These derangements are reversed by ezetimibe, but not statins, which are currently the first line of lipid-lowering treatment in type 1 diabetes. Taken together, these data suggest that a personalized approach to lipid lowering in type 1 diabetes may be more effective and highlight the need for further studies specifically in this group of patients.
MeSH term(s)	Animals ; Bile Acids and Salts/metabolism ; Cholesterol, LDL ; Cross-Over Studies ; Diabetes Mellitus, Type 1/drug therapy ; Diabetes Mellitus, Type 1/metabolism ; Diabetes Mellitus, Type 1/prevention & control ; Ezetimibe/pharmacology ; Ezetimibe/therapeutic use ; Humans ; Hypercholesterolemia/drug therapy ; Hypercholesterolemia/genetics ; Hyperlipidemias ; Insulin ; Liver/metabolism ; Mice ; Receptor, Insulin/genetics ; Receptor, Insulin/metabolism ; Simvastatin/pharmacology ; Simvastatin/therapeutic use ; Steroid 12-alpha-Hydroxylase/genetics ; Steroid 12-alpha-Hydroxylase/metabolism
Chemical Substances	Bile Acids and Salts ; Cholesterol, LDL ; Insulin ; Simvastatin (AGG2FN16EV) ; Steroid 12-alpha-Hydroxylase (EC 1.14.18.8) ; Receptor, Insulin (EC 2.7.10.1) ; Ezetimibe (EOR26LQQ24)
Language	English
Publishing date	2022-02-23
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80099-5
ISSN	1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
ISSN (online)	1524-4539
ISSN	0009-7322 ; 0069-4193 ; 0065-8499
DOI	10.1161/CIRCULATIONAHA.120.045373
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Article ; Online: FoxO1 Is Required for Most of the Metabolic and Hormonal Perturbations Produced by Hepatic Insulin Receptor Deletion in Male Mice.

Ling, Alisha V / Gearing, Mary E / Semova, Ivana / Shin, Dong-Ju / Clements, Rebecca / Lai, Zon W / Biddinger, Sudha B

Endocrinology

2018 Volume 159, Issue 3, Page(s) 1253–1263

Abstract: Insulin coordinates the complex response to feeding, affecting numerous metabolic and hormonal pathways. Forkhead box protein O1 (FoxO1) is one of several signaling molecules downstream of insulin; FoxO1 drives gluconeogenesis and is suppressed by ... ...

Abstract	Insulin coordinates the complex response to feeding, affecting numerous metabolic and hormonal pathways. Forkhead box protein O1 (FoxO1) is one of several signaling molecules downstream of insulin; FoxO1 drives gluconeogenesis and is suppressed by insulin. To determine the role of FoxO1 in mediating other actions of insulin, we studied mice with hepatic deletion of the insulin receptor, FoxO1, or both. We found that mice with deletion of the insulin receptor alone showed not only hyperglycemia but also a 70% decrease in plasma insulin-like growth factor 1 and delayed growth during the first 2 months of life, a 24-fold increase in the soluble leptin receptor and a 19-fold increase in plasma leptin levels. Deletion of the insulin receptor also produced derangements in fatty acid metabolism, with a decrease in the expression of the lipogenic enzymes, hepatic diglycerides, and plasma triglycerides; in parallel, it increased expression of the fatty acid oxidation enzymes. Mice with deletion of both insulin receptor and FoxO1 showed a much more modest phenotype, with normal or near-normal glucose levels, growth, leptin levels, hepatic diglycerides, and fatty acid oxidation gene expression; however, lipogenic gene expression remained low. Taken together, these data reveal the pervasive role of FoxO1 in mediating the effects of insulin on not only glucose metabolism but also other hormonal signaling pathways and even some aspects of lipid metabolism.
MeSH term(s)	Animals ; Blood Glucose/analysis ; Fatty Acids/metabolism ; Forkhead Box Protein O1/deficiency ; Forkhead Box Protein O1/genetics ; Forkhead Box Protein O1/physiology ; Gene Expression ; Gluconeogenesis/genetics ; Insulin/blood ; Insulin/pharmacology ; Insulin/physiology ; Insulin-Like Growth Factor I/metabolism ; Leptin/blood ; Leptin/metabolism ; Lipids/analysis ; Lipogenesis/genetics ; Liver/chemistry ; Liver/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Oxidation-Reduction ; Receptor, Insulin/deficiency ; Receptor, Insulin/physiology ; Receptors, Leptin/blood ; Triglycerides/blood
Chemical Substances	Blood Glucose ; Fatty Acids ; Forkhead Box Protein O1 ; Insulin ; Leptin ; Lipids ; Receptors, Leptin ; Triglycerides ; Insulin-Like Growth Factor I (67763-96-6) ; Receptor, Insulin (EC 2.7.10.1)
Language	English
Publishing date	2018-01-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/en.2017-00870
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Article ; Online: Nonalcoholic fatty liver disease and gastric bypass surgery regulate serum and hepatic levels of pyruvate kinase isoenzyme M2.

Meoli, Luca / Gupta, Nitin K / Saeidi, Nima / Panciotti, Courtney A / Biddinger, Sudha B / Corey, Kathleen E / Stylopoulos, Nicholas

American journal of physiology. Endocrinology and metabolism

2018 Volume 315, Issue 4, Page(s) E613–E621

Abstract: Treatment of nonalcoholic fatty liver disease (NAFLD) focuses on the underlying metabolic syndrome, and Roux-en-Y gastric bypass surgery (RYGB) remains one of the most effective options. In rodents and human patients, RYGB induces an increase in the gene ...

Abstract	Treatment of nonalcoholic fatty liver disease (NAFLD) focuses on the underlying metabolic syndrome, and Roux-en-Y gastric bypass surgery (RYGB) remains one of the most effective options. In rodents and human patients, RYGB induces an increase in the gene and protein expression levels of the M2 isoenzyme of pyruvate kinase (PKM2) in the jejunum. Since PKM2 can be secreted in the circulation, our hypothesis was that the circulating levels of PKM2 increase after RYGB. Our data, however, revealed an unexpected finding and a potential new role of PKM2 for the natural history of metabolic syndrome and NAFLD. Contrary to our initial hypothesis, RYGB-treated patients had decreased PKM2 blood levels compared with a well-matched group of patients with severe obesity before RYGB. Interestingly, PKM2 serum concentration correlated with body mass index before but not after the surgery. This prompted us to evaluate other potential mechanisms and sites of PKM2 regulation by the metabolic syndrome and RYGB. We found that in patients with NAFLD and nonalcoholic steatohepatitis (NASH), the liver had increased PKM2 expression levels, and the enzyme appears to be specifically localized in Kupffer cells. The study of murine models of metabolic syndrome and NASH replicated this pattern of expression, further suggesting a metabolic link between hepatic PKM2 and NAFLD. Therefore, we conclude that PKM2 serum and hepatic levels increase in both metabolic syndrome and NAFLD and decrease after RYGB. Thus, PKM2 may represent a new target for monitoring and treatment of NAFLD.
MeSH term(s)	Adult ; Animals ; Carrier Proteins/metabolism ; Disease Models, Animal ; Female ; Gastric Bypass ; Humans ; Jejunum/metabolism ; Liver/metabolism ; Male ; Membrane Proteins/metabolism ; Metabolic Syndrome/metabolism ; Mice ; Middle Aged ; Non-alcoholic Fatty Liver Disease/metabolism ; Obesity/metabolism ; Obesity/surgery ; Pyruvate Kinase/metabolism ; Thyroid Hormones/metabolism ; Thyroid Hormone-Binding Proteins
Chemical Substances	Carrier Proteins ; Membrane Proteins ; Thyroid Hormones ; Pkm protein, mouse (EC 2.7.1.40) ; Pyruvate Kinase (EC 2.7.1.40)
Language	English
Publishing date	2018-02-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	603841-4
ISSN	1522-1555 ; 0193-1849
ISSN (online)	1522-1555
ISSN	0193-1849
DOI	10.1152/ajpendo.00296.2017
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Article ; Online: YAP suppresses gluconeogenic gene expression through PGC1α.

Hu, Yue / Shin, Dong-Ju / Pan, Hui / Lin, Zhiqiang / Dreyfuss, Jonathan M / Camargo, Fernando D / Miao, Ji / Biddinger, Sudha B

Hepatology (Baltimore, Md.)

2017 Volume 66, Issue 6, Page(s) 2029–2041

Abstract: Cell growth and proliferation are tightly coupled to metabolism, and dissecting the signaling molecules which link these processes is an important step toward understanding development, regeneration, and cancer. The transcriptional regulator Yes- ... ...

Abstract	Cell growth and proliferation are tightly coupled to metabolism, and dissecting the signaling molecules which link these processes is an important step toward understanding development, regeneration, and cancer. The transcriptional regulator Yes-associated protein 1 (YAP) is a key regulator of liver size, development, and function. We now show that YAP can also suppress gluconeogenic gene expression. Yap deletion in primary hepatocytes potentiates the gluconeogenic gene response to glucagon and dexamethasone, whereas constitutively active YAP suppresses it. The effects of YAP are mediated by the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1. YAP inhibits its ability to bind to and activate transcription from the promoters of its gluconeogenic targets, and the effects of YAP are blunted upon its knockdown. In vivo, constitutively active YAP lowers plasma glucose levels and increases liver size. Conclusion: YAP appears to reprogram cellular metabolism, diverting substrates away from the energy-consuming process of gluconeogenesis and toward the anabolic process of growth. (Hepatology 2017;66:2029-2041).
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Carcinoma, Hepatocellular/metabolism ; Cell Cycle Proteins ; Gene Expression Regulation ; Gluconeogenesis/genetics ; Glucose-6-Phosphatase/metabolism ; Hep G2 Cells ; Humans ; Liver Neoplasms/metabolism ; Male ; Mice ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Phosphoenolpyruvate Carboxykinase (GTP)/metabolism ; Phosphoproteins/metabolism ; Primary Cell Culture ; Random Allocation ; Transcription Factors
Chemical Substances	Adaptor Proteins, Signal Transducing ; Cell Cycle Proteins ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Phosphoproteins ; Ppargc1a protein, mouse ; Transcription Factors ; YAP1 protein, human ; Yap1 protein, mouse ; Glucose-6-Phosphatase (EC 3.1.3.9) ; Phosphoenolpyruvate Carboxykinase (GTP) (EC 4.1.1.32)
Language	English
Publishing date	2017-10-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	604603-4
ISSN	1527-3350 ; 0270-9139
ISSN (online)	1527-3350
ISSN	0270-9139
DOI	10.1002/hep.29373
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Article ; Online: Markers of cholesterol synthesis are elevated in adolescents and young adults with type 2 diabetes.

Semova, Ivana / Levenson, Amy E / Krawczyk, Joanna / Bullock, Kevin / Williams, Kathryn A / Wadwa, R Paul / Khoury, Philip R / Kimball, Thomas R / Urbina, Elaine M / de Ferranti, Sarah D / Maahs, David M / Dolan, Lawrence M / Shah, Amy S / Clish, Clary B / Biddinger, Sudha B

Pediatric diabetes

2020 Volume 21, Issue 7, Page(s) 1126–1131

Abstract: Background: Changes in cholesterol absorption and cholesterol synthesis may promote dyslipidemia and cardiovascular disease in individuals with type 2 diabetes mellitus (T2DM).: Objective: To assess cholesterol synthesis and absorption in lean ... ...

Abstract	Background: Changes in cholesterol absorption and cholesterol synthesis may promote dyslipidemia and cardiovascular disease in individuals with type 2 diabetes mellitus (T2DM). Objective: To assess cholesterol synthesis and absorption in lean individuals, obese individuals, and individuals with T2DM. Methods: We measured lathosterol and lanosterol (markers of cholesterol synthesis) as well as campesterol and β-sitosterol (markers of cholesterol absorption) in the serum of 15 to 26 years old individuals with T2DM (n = 95), as well as their lean (n = 98) and obese (n = 92) controls. Results: Individuals with T2DM showed a 51% increase in lathosterol and a 65% increase in lanosterol compared to lean controls. Similarly, obese individuals showed a 31% increase in lathosterol compared to lean controls. Lathosterol and lanosterol were positively correlated with body mass index, fasting insulin and glucose, serum triglycerides, and C-reactive protein, and negatively correlated with HDL-cholesterol. In contrast, campesterol and β-sitosterol were not altered in individuals with T2DM. Moreover, campesterol and β-sitosterol were negatively correlated with body mass index, fasting insulin, and C-reactive protein and were positively correlated with HDL-cholesterol. Conclusions: Adolescents and young adults with T2DM show evidence of increased cholesterol synthesis compared to non-diabetic lean controls. These findings suggest that T2DM may promote cardiovascular disease by increasing cholesterol synthesis, and provide additional rationale for the use of cholesterol synthesis inhibitors in this group.
MeSH term(s)	Adolescent ; Adult ; Biomarkers ; Body Mass Index ; Case-Control Studies ; Cholesterol/analogs & derivatives ; Cholesterol/blood ; Cholesterol/metabolism ; Diabetes Mellitus, Type 2/blood ; Diabetes Mellitus, Type 2/complications ; Humans ; Obesity/blood ; Obesity/complications ; Phytosterols/blood ; Sitosterols/blood ; Young Adult
Chemical Substances	Biomarkers ; Phytosterols ; Sitosterols ; campesterol (5L5O665639) ; gamma-sitosterol (5LI01C78DD) ; lathosterol (80-99-9) ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2020-09-15
Publishing country	Denmark
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1502504-4
ISSN	1399-5448 ; 1745-1426 ; 1399-543X
ISSN (online)	1399-5448
ISSN	1745-1426 ; 1399-543X
DOI	10.1111/pedi.13097
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