Overview of the two components of lipid metabolism

Detailed Illustration of the lipoprotein metabolism in the human body. Chol: Cholesterol, CM: Chylomicrons, CMR: Chylomicrone Remnants, TAG: Triacylglycerol, FFA: Free Fatty Acids, HDL: High Density lipoprotein, LDL: Low Density Lipoprotein, VLDL: Very Low Density Lipoprotein, LPL: Lipoprotein Lipase, HL: Hepatic Lipase, LCAT: Lecithin cholesterol acyltransferase, CETP: Cholesteryl ester transfer protein, LDLR: LDL-Receptor

Detailed Illustration of intracellular Lipid Metabolism. HMG-CoA-R: HMG-CoA-Reductase, ATGL: Adipose Triglyceride Lipase, HSL: Hormone Sensitive Lipase, MGL: Monoglyceride Lipase, FA: FAtty Acids

The endocrine system exerts extensive control over both domains. Because of this, disturbances in hormonal signaling lead to characteristic changes in circulating lipids. Although considerable overlap exists across endocrine disorders, lipid profiles can still offer meaningful clues to an underlying hormonal imbalance. To illustrate this, consider the following three representative lipid patterns. Try to match each one to the most likely endocrine dysfunction.

• Insulin Deficiency/Resistance

• Hypothyroidism

• GH-Deficiency

Before revealing the answers, we will outline the physiological and pathophysiological basis by which these endocrine disorders alter lipid homeostasis. Insulin, growth hormone, and thyroid hormones each regulate lipid metabolism at distinct and complementary control points, and their deficiency or impaired signaling produces predictable dyslipidemic patterns.

Insulin

Effects on intracellular lipid metabolism:

Insulin plays a central role in promoting lipid storage and suppressing lipid mobilization. It stimulates fatty-acid synthesis in the liver and adipose tissue by activating key enzymes and enhances the transcription of lipogenic genes. At the same time, insulin inhibits hormone-sensitive lipase, thereby reducing the release of free fatty acids (FFAs) from adipose tissue.

Pathophysiology: Insulin deficiency or impaired signaling leads to a loss of this anti-lipolytic effect, increasing adipose tissue lipolysis and raising FFA flux to the liver. This altered substrate availability subsequently impacts lipoprotein metabolism, as discussed below.

Physiological and pathophysiological effects of insulin and Insulin deficiency on intracellular Lipid Metabolism. HMG-CoA-R: HMG-CoA-Reductase, ATGL: Adipose Triglyceride Lipase, HSL: Hormone Sensitive Lipase, MGL: Monoglyceride Lipase, FA: FAtty Acids

Effects on lipoprotein metabolism:

FFAs delivered to the liver are used for VLDL synthesis and secretion. In insulin deficiency, the increased FFA supply drives excessive VLDL production, manifesting as hypertriglyceridemia.

In addition, insulin activity normally enhances lipoprotein lipase (LPL) function in peripheral tissues, promoting the clearance of triglyceride-rich lipoproteins such as VLDL and chylomicrons. In deficiency states, LPL activity is reduced, further contributing to accumulation of VLDL and chylomicrons, exacerbating hypertriglyceridemia.

The combination of increased production and decreased clearance results in an accumulation of triglyceride-rich particles and promotes the formation of small, dense LDL, which are particularly atherogenic.

Insulin also broadly regulates lipoprotein composition by supporting hepatic LDL receptor activity and promoting HDL formation. Consequently, insulin deficiency reduces LDL clearance and lowers HDL cholesterol levels..

This constellation of elevated triglycerides, low HDL cholesterol, and small dense LDL particles (may result in mild increase of LDL-Cholesterol) forms the characteristic dyslipidemic pattern of insulin deficiency, insulin resistance, and hyperglycemia.

Physiological and pathophysiological effects of insulin and Insulin deficiency on the lipoprotein metabolism in the human body. Chol: Cholesterol, CM: Chylomicrons, CMR: Chylomicrone Remnants, TAG: Triacylglycerol, FFA: Free Fatty Acids, HDL: High Density lipoprotein, LDL: Low Density Lipoprotein, VLDL: Very Low Density Lipoprotein, LPL: Lipoprotein Lipase, HL: Hepatic Lipase, LCAT: Lecithin cholesterol acyltransferase, CETP: Cholesteryl ester transfer protein, LDLR: LDL-Receptor

Growth Hormone

Effects on Intracellular Lipid Metabolism

GH exerts primarily lipolytic effects in adipose tissue, stimulating triglyceride breakdown and increasing circulating FFAs. GH antagonizes insulin’s anti-lipolytic action, promoting fatty-acid flux and potentially contributing to insulin resistance. In the liver, GH modulates the expression of lipogenic enzymes and influences triglyceride secretion. Insulin can partially attenuate GH-mediated stimulation of hepatic lipogenesis and triglyceride production.

Pathophysiology: GH deficiency reduces these lipolytic and metabolic effects, leading to increased fat accumulation, particularly visceral adiposity and hepatic steatosis.

Physiological and pathophysiological effects of GH and GH deficiency on intracellular Lipid Metabolism. HMG-CoA-R: HMG-CoA-Reductase, ATGL: Adipose Triglyceride Lipase, HSL: Hormone Sensitive Lipase, MGL: Monoglyceride Lipase, FA: FAtty Acids

Effects on Lipoprotein Metabolism

GH normally upregulates hepatic LDL receptor expression and reduces PCSK9, enhancing LDL clearance. This also facilitates the hepatic uptake and catabolism of VLDL and its apolipoprotein B-100 (apoB-100) component, leading to increased VLDL clearance.

Pathophysology: In GH deficiency, reduced LDL receptor activity leads to higher circulating LDL and VLDL cholesterol. The latter is the main reason for hypertriglyceridemia in GH deficiency.

Changes in body composition, specifically increased visceral fat and reduced lean mass, further worsen dyslipidemia.

The net effect in GH deficiency is an increase in LDL-C, VLDL, and triglycerides, sometimes accompanied by reduced HDL cholesterol.

Physiological and pathophysiological effects of GH and GH deficiency on the lipoprotein metabolism in the human body. Chol: Cholesterol, CM: Chylomicrons, CMR: Chylomicrone Remnants, TAG: Triacylglycerol, FFA: Free Fatty Acids, HDL: High Density lipoprotein, LDL: Low Density Lipoprotein, VLDL: Very Low Density Lipoprotein, LPL: Lipoprotein Lipase, HL: Hepatic Lipase, LCAT: Lecithin cholesterol acyltransferase, CETP: Cholesteryl ester transfer protein, LDLR: LDL-Receptor

Thyroid Hormones

Effects on Intracellular Lipid Metabolism

Thyroid hormones regulate both lipid synthesis and degradation. They increase lipolysis and fatty-acid β-oxidation, while modulating de novo lipogenesis through transcriptional control of enzymes and regulators.

Pathophysiology: Hypothyroidism reduces these effects, leading to lower fatty-acid oxidation, decreased triglyceride hydrolysis, and impaired intracellular lipid turnover resulting in reduced lipolysis and increased lipid accumulation.

Physiological and pathophysiological effects of TH and Hypothyroidism on intracellular Lipid Metabolism. HMG-CoA-R: HMG-CoA-Reductase, ATGL: Adipose Triglyceride Lipase, HSL: Hormone Sensitive Lipase, MGL: Monoglyceride Lipase, FA: FAtty Acids

Effects on Lipoprotein Metabolism

Thyroid hormones enhance hepatic LDL receptor expression, increasing LDL clearance, and stimulate cholesterol 7α-hydroxylase, promoting bile acid synthesis. Thyroid hormones increase Lipoprotein Lipase (LPL) activity, promoting VLDL Clearance. They also promote HDL production by maintaining Cholesteryl ester transfer protein (CETP) function.

Pathophysiology: Hypothyroidism reduces LDL receptor activity and bile acid production, resulting in elevated LDL-C and total cholesterol.

Decreased Lipoprotein lipase activity impaires clearance of triglyceride-rich lipoproteins leading to moderate hypertriglyceridemia. Patients with hypothyroidism may have variable, often low HDL cholesterol levels.

Physiological and pathophysiological effects of TH and Hypothyroidism on the lipoprotein metabolism in the human body. Chol: Cholesterol, CM: Chylomicrons, CMR: Chylomicrone Remnants, TAG: Triacylglycerol, FFA: Free Fatty Acids, HDL: High Density lipoprotein, LDL: Low Density Lipoprotein, VLDL: Very Low Density Lipoprotein, LPL: Lipoprotein Lipase, HL: Hepatic Lipase, LCAT: Lecithin cholesterol acyltransferase, CETP: Cholesteryl ester transfer protein, LDLR: LDL-Receptor

In summary, Insulin Deficiency/Resistance, GH Deficiency and Hypothyroidism therefore typically lead to the following lipid profiles:

References

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