Insulin Prevents Hypercholesterolemia by Suppressing 12α-Hydroxylated Bile Acids

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 statins in a double-blind crossover study. Results: Mice with hepatic deletion of the insulin receptor showed marked increases in 12α-hydroxylated bile acids (12HBAs), cholesterol absorption, and plasma cholesterol. This phenotype was entirely reversed by hepatic deletion of FoxO1 . FoxO1 is inhibited by insulin, and required for the production of 12HBAs, which promote intestinal cholesterol absorption and suppress hepatic cholesterol synthesis. Knockdown of Cyp8b1 normalized 12HBA levels and completely prevented hypercholesterolemia in mice with hepatic deletion of the insulin receptor (n=5-30) as well as mouse models of type 1 diabetes (n=5-22). In parallel, the cholesterol absorption inhibitor, ezetimibe, normalized cholesterol absorption and LDL-cholesterol in patients with type 1 diabetes as well as, or better than, the cholesterol synthesis inhibitor, simvastatin (n=20). Conclusions: Insulin, by inhibiting FoxO1 in the liver, reduces 12HBAs, 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.

The relationship between the number of stenotic coronary arteries and the gut microbiome in coronary heart disease patients

“…In addition, spearman correlation coefficient analysis showed that the genus Escherichia-Shigella was positively correlated with LDL and LA, and negatively correlated with TBA. A new study showed that bile acid could promote intestinal cholesterol absorption and suppress hepatic cholesterol synthesis to prevent hypercholesterolemia (Semova et al, 2022). High levels of LDL are recognized as one of the risk factors leading to the occurrence and development of coronary heart disease.…”

The Remnant Lipoprotein Hypothesis of Diabetes-Associated Cardiovascular Disease

“…50,77 A recent study demonstrated that hepatic insulin receptors also play a role in preventing intestinal cholesterol absorption. 78 This effect of hepatic insulin receptors was due to suppression of 12α-hydroxylated bile acid production 78 mediated by suppression of the transcription factor FoxO1. 79 Thus, silencing of the enzyme Cyp8b1, which generates 12α-hydroxylated bile acid, prevented hypercholesterolemia in mice with hepatic deletion of the insulin receptor and in a mouse model of T1D.…”

Insulin and Bile Acids in Cholesterol Homeostasis: New Players in Diabetes-Associated Atherosclerosis

“…As expected, ezetimibe ameliorated these parameters in this cohort of patients. 2 From a clinical perspective, macrovascular disease continues to be a major burden for patients with diabetes, and cholesterol-lowering therapy has been shown to decrease both events and mortality. 13 It is important to note that although most prospective evidence derives from studies in patients with type 2 diabetes, small clinical trials and observational evidence support the efficacy and safety of cholesterol-lowering therapy in patients with T1D.…”

“…In the intestine, increased CA/CDCA ratio favors cholesterol absorption, which ultimately leads to higher circulating low-density lipoprotein cholesterol and increased atherosclerosis risk. The findings of Semova et al 2 are highlighted in blue. IR indicates insulin resistance.…”

“…In a further expansion of this research, Semova et al 2 describe in this issue of Circulation how in the liver insulin decreases the relative amount of 12α-hydroxylated BAs (12 HBAs), leading to reduced cholesterol absorption. The authors go on to propose that states of insulin deficiency such as type 1 diabetes (T1D) are characterized by increased cholesterol absorption leading to hypercholesterolemia, which could be reversed by the blockade of intestinal cholesterol absorption, for example, with ezetimibe.…”