Research Blog

September 15, 2020

Oxidative Stress part 5 - The Cholesterol Connection

Oxidative stress: Counteracted by cholesterol?!

Dicken Weatherby, N.D. and Beth Ellen DiLuglio, MS, RDN, LDN

Cholesterol acts as an antioxidant

Early research identifies cholesterol itself as an antioxidant that protects cells from free radical damage. Oxidative damage can, in turn, deplete cholesterol and disrupt cell membrane function.[i]

The ODX Oxidative Stress Series

  1. Oxidative Stress part 1 - And You Thought You Were Stressed!
  2. Oxidative Stress part 2 - Blood Biomarkers: Functional Blood Chemistry Clues
  3. Oxidative Stress part 3 - Specialized Markers Provide More Clues
  4. Oxidative Stress part 4 - Cardiometabolic Disease & Oxidative Stress
  5. Oxidative Stress part 5 - The Cholesterol Connection
  6. Oxidative Stress part 6 - Glutathione Inside and Out
  7. Optimal - The Podcast: Episode 1 Oxidative Stress

Cholesterol Intercepts oxidants and produces oxysterol compounds. This may be considered a normal part of metabolism. Oxysterol derivatives are metabolized by the liver and excreted in bile and feces. Excess oxidative stress will produce excess oxysterols

In atherosclerosis, the problem isn’t necessarily the presence of cholesterol but the presence of EXCESS oxidants[ii]

Researchers suggest that the production of oxysterols (oxidized cholesterol derivatives) are present because cholesterol is intercepting oxidants as a normal part of metabolism. These derivatives are metabolized by the liver and excreted in the bile and feces. Excess exposure to oxidants can be expected to favor excess production of oxysterols.

Oxidation of low density lipoprotein/LDL and atherosclerotic plaque[iii]

Oxidative stress, hyperglycemia, hypertriglyceridemia, and low AOP contribute to oxidation of LDL and atherosclerosis. Elevated triglycerides increase oxidizability of LDL while HDL reduces oxidizability. The oxidation of LDL induces accumulation of LDL cholesterol and an inflammatory response. Under preferred conditions, LDL contains antioxidant compounds such as alpha-tocopherol, beta-carotene, and CoQ10 that protect it from oxidation and determine antioxidant potential (AOP). A reduced AOP sets the stage for a vicious cycle of increased oxidative stress and lipid peroxidation.

In 100 diabetic patients, AOP was significantly decreased and sensitivity to LDL oxidation was significantly increased regardless of controlled or uncontrolled hemoglobin A1C compared to controls.

Low HDL-C permits excess oxidative stress[iv]

HDL-C exerts important antioxidant, anti-inflammatory, and anti-atherogenic properties activities that protect against cardiovascular disease. Low serum HDL-C is an independent risk factor for early atherosclerosis and coronary heart disease and is associated with increased oxidative stress. A matched control study looked at oxidative stress in low HDL (35 mg/dL or less) versus controls with an HDL-C of greater than 35 mg/dL (0.9 mmol/L). HDL-C levels were significantly lower in study group at 30 +/- 3 mg/dL (0.78 +/- 0.08 mmol/L) than in controls at 48 +/- 7 mg dL, p< 0.01 (1.24 +/- 0.18 mmol/L)

Low HDL subjects had

  • Significantly higher ALT, GGT, uric acid, total oxidative status
  • Higher triglycerides
  • Increased oxidative stress with significantly lower total antioxidant capacity/TAC (p<0.01) and higher oxidative stress index/OSI (p<0.06)
  • Interestingly controls had significantly higher total cholesterol and LDL

Small, dense, protein-rich HDL particles protect LDL from oxidation and scavenge lipid hydroperoxides. The antioxidant function of HDL can be impaired in metabolic and inflammatory disease.[v]

Is Low cholesterol detrimental?

In a Turkish study of young healthy adults, oxidative stress index was statistically correlated with mean total cholesterol below 180 mg/dL (4.65 mmol/L) and elevated LDL above 132 mg/dL (3.42 mmol/L).[vi]

Research on serum cholesterol and mortality in the elderly revealed that the lowest cholesterol quartile of 149 mg/dL (3.85 mmol/L) was significantly associated with mortality compared to higher quartiles of 178 mg/dL (4.61 mmol/L), 199 mg/dL (5.15 mmol/L), and 231 mg/dL (5.99 mmol/L).

Researchers question the practice of reducing serum cholesterol below 180 mg/dL (4.65 mmol/L) in the elderly.[vii]


We need cholesterol, and we need to protect it with plenty of antioxidants from the diet, from endogenous production, and from supplementation when needed.

Up Next - Oxidative Stress and Glutathione


[i] Butterfield, J D Jr, and C P McGraw. “Free radical pathology.” Stroke vol. 9,5 (1978): 443-5. doi:10.1161/01.str.9.5.443 [R]

[ii] Smith, L L. “Another cholesterol hypothesis: cholesterol as antioxidant.” Free radical biology & medicine vol. 11,1 (1991): 47-61. doi:10.1016/0891-5849(91)90187-8 [R]

[iii] Singh, Nivedita et al. “Reduced Antioxidant Potential of LDL Is Associated With Increased Susceptibility to LDL Peroxidation in Type II Diabetic Patients.” International journal of endocrinology and metabolism vol. 10,4 (2012): 582-6. doi:10.5812/ijem.5029 [R] 

[iv] Karabacak, Mustafa, et al. "Low HDL Cholesterol Situations is Characterised by Elevated Oxidative Stress." Journal of the American College of Cardiology 62.18 Supplement 2 (2013): C181.  [R]

[v] Brites, Fernando et al. “Antioxidative activity of high-density lipoprotein (HDL): Mechanistic insights into potential clinical benefit.” BBA clinical vol. 8 66-77. 19 Aug. 2017, doi:10.1016/j.bbacli.2017.07.002 [R]

[vi] Turkdogan, Kenan Ahmet et al. “Association between oxidative stress index and serum lipid levels in healthy young adults.” JPMA. The Journal of the Pakistan Medical Association vol. 64,4 (2014): 379-81. [R]

[vii] Schatz, I J et al. “Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study.” Lancet (London, England) vol. 358,9279 (2001): 351-5. doi:10.1016/S0140-6736(01)05553-2 [R]

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