NSC 408: Cholesterol

Cholesterol Metabolism and Functions

Introduction to Lipids and Sterols

• From lecture 3.2, four types of lipids and their variations were discussed:

  • Fatty acids: These were covered in a prior lecture.

    • Variations in fatty acids include carbon chain length, saturation/unsaturation, and double bond configuration (cis vs. trans).

  • Triglycerides (TGs)

  • Phospholipids

  • Sterols

• Key Question: What are the functions of sterols? (Refer to Flexbook: Figure 2.371)

Cholesterol as a Precursor to Hormones and Vitamin D

• Cholesterol is a fundamental precursor molecule for a variety of critical biological compounds, including steroid hormones and Vitamin D.

• Steroid Hormone Synthesis Pathway:

  • The conversion of cholesterol into various steroid hormones is a multi-step enzymatic process involving specific cytochrome P450 enzymes and hydroxysteroid dehydrogenases.

  • Initial Steps: Cholesterol is first hydroxylated at the $22R$-position to form $22R$-Hydroxycholesterol, followed by further hydroxylation at the $20R$-position to yield $20R,22R$-Dihydroxycholesterol. Both steps are catalyzed by $CYP11A1$. This intermediate is then converted to Pregnenolone by $CYP11A1$.

  • Progesterone Production: Pregnenolone can be transformed into Progesterone by the enzyme $HSD3B1/2$.

  • Corticosteroid Synthesis (e.g., Cortisol, Aldosterone):

    • Pregnenolone can be converted to $17\alpha$-Hydroxypregnenolone by $CYP17A1$. This can then be converted to $17\alpha$-Hydroxyprogesterone by $HSD3B2$. $17\alpha$-Hydroxyprogesterone is a precursor to 11-Deoxycortisol (via $CYP21A2$) and subsequently Cortisol (via $CYP11B1$).

    • Progesterone can also lead to 11-Deoxycorticosterone (via $CYP21A2$), then Corticosterone (via $CYP11B1/2$), and finally Aldosterone (via $CYP11B2$).

    • Cortisol can be metabolized to Cortisone by $HSD11B2$ and further reduced to Tetrahydrocortisol by $SDR5A2/AKR1D1$.

    • Corticosterone can be reduced to Tetrahydrocorticosterone by $SDR5A2/AKR1D1$.

  • Androgen Synthesis (e.g., Testosterone):

    • $17\alpha$-Hydroxypregnenolone is a precursor to Dehydroepiandrosterone (DHEA) via $CYP17A1$. DHEA can be sulfated to Dehydroepiandrosterone sulfate by $SULT2A1$.

    • DHEA is converted to Androstenedione by $HSD3B2$.

    • Androstenedione is converted to Testosterone by $HSD17B3$. Testosterone can then be reduced to $5\alpha$-Dihydrotestosterone by $SRD5A2$.

  • Estrogen Synthesis (e.g., Estrone, $17\beta$-Estradiol):

    • Androstenedione can be aromatized to Estrone by $CYP19A1$.

    • Testosterone can be aromatized to $17\beta$-Estradiol by $CYP19A1$.

    • Estrone and $17\beta$-Estradiol can interconvert through the action of $HSD17B2/4$ and $HSD17B1$ enzymes.

  • Additional Metabolite: $7\alpha$-Hydroxydehydroepiandrosterone can be formed from DHEA via $CYP7B1$.

• Vitamin D Synthesis Pathway:

  • $7$-Dehydrocholesterol, a sterol structurally similar to cholesterol, is converted into Previtamin D$3$ upon exposure to Ultraviolet light.

  • Previtamin D$3$ spontaneously isomerizes through a non-enzymatic thermal rearrangement to form Vitamin D$3$ (Cholecalciferol).

  • Vitamin D$3$ undergoes further hydroxylation steps in the liver and kidneys to become Calcitriol ($1,25$-Dihydroxycholecalciferol), which is the biologically active form of Vitamin D.

Synthesis of Cholesterol

• Integration with Macronutrient Metabolism: Acetyl-CoA is a pivotal molecule in metabolism, serving as the starting material for cholesterol synthesis and integrating pathways from carbohydrates, fats, and proteins.

• **Three Key Steps in Cholesterol Synthesis (Flexbook: Figure 6.351 & 6.352):

  1. Acetyl-CoA ($CH_3COSCoA$) is first converted to Acetoacetyl-CoA, which is a molecule with $4$ carbons.

  2. Acetoacetyl-CoA then forms $3$-hydroxy-$3$-methylglutaryl-CoA (HMG-CoA).

  3. HMG-CoA is subsequently converted to Mevalonate by the enzyme HMG-CoA reductase. This enzyme is recognized as the rate-limiting enzyme in the entire cholesterol synthesis pathway.

Cholesterol Excretion and Reverse Cholesterol Transport

• Cholesterol is ultimately eliminated from the body through excretion in feces. This process is a crucial component of reverse cholesterol transport, where excess cholesterol is moved from peripheral tissues back to the liver, converted to bile acids, and then expelled.

• Targeting Strategies to Lower LDL Cholesterol (Practical Implications):

  • Increase $CYP7A1$ activity: $CYP7A1$ (cholesterol $7\alpha$-hydroxylase) is the rate-limiting enzyme in the classic pathway of bile acid biosynthesis from cholesterol. Enhancing its activity increases the conversion of cholesterol into bile acids, thereby reducing overall cholesterol levels.

  • Decrease $ABST$ enzyme activity: $ABST$ (Apical Sodium-dependent Bile acid Transporter) is responsible for reabsorbing bile acids from the intestinal lumen back into the enterohepatic circulation. Inhibiting $ABST$ reduces bile acid reabsorption, leading to increased fecal excretion of bile acids, which, in turn, stimulates the liver to synthesize more bile acids from cholesterol.

  • Consume Soluble Fiber: Soluble dietary fiber can bind to bile acids within the intestine. This binding prevents the reabsorption of bile acids, promoting their excretion. As with $ABST$ inhibition, this process forces the liver to convert more cholesterol into new bile acids, lowering cholesterol levels.

  • (Reference: Chambers, K. F., Day, P. E., Aboufarrag, H. T., & Kroon, P. A. (2019). Polyphenol Effects on Cholesterol Metabolism via Bile Acid Biosynthesis, CYP7A1: A Review. Nutrients, 11(11), 2588. https://doi.org/10.3390/nu11112588)

Regulation of Cholesterol Synthesis

• The body maintains tight homeostatic control over cholesterol levels through feedback mechanisms.

• When Cholesterol Levels in Circulation are Too Low:

  • The body responds by increasing its endogenous synthesis of cholesterol from Acetyl-CoA.

  • Concurrently, there is an increase in the intestinal reuptake of bile acids, conserving existing cholesterol resources.

• When Cholesterol Levels in Circulation are Too High:

  • The body reduces its own cholesterol synthesis from Acetyl-CoA.

  • It increases the excretion of cholesterol into bile.

  • Intestinal reuptake of bile acids is reduced, promoting their fecal elimination and consequently increasing the demand for cholesterol to synthesize new bile acids.

• Discussion Point: The question of whether dietary cholesterol significantly impacts circulating cholesterol levels is a topic for consideration and ongoing research.