The liver-protective effect of hydroxytyrosol

Hepatoprotective Effects of Hydroxytyrosol: Intervention in Non-Alcoholic Fatty Liver Disease and Oxidative Stress

I. Pathological Association Between Non-Alcoholic Fatty Liver Disease (NAFLD) and Oxidative Stress

NAFLD is closely linked to lipid metabolism disorders, oxidative stress, and inflammatory responses. Excessive hepatic lipid deposition (especially triglycerides) induces massive reactive oxygen species (ROS) production in hepatocytes, disrupting the oxidative-antioxidative balance. ROS attack membrane lipids, proteins, and DNA, causing hepatocyte damage and apoptosis, and further promoting liver fibrosis. Additionally, oxidative stress interferes with insulin signaling pathways, exacerbating metabolic disorders and forming an "oxidative-metabolic" vicious cycle.

II. Hepatoprotective Mechanisms of Hydroxytyrosol: Targeting Oxidative Stress and Lipid Metabolism

Hydroxytyrosol, a major polyphenol in olive oil and its processed products, exhibits significant potential in NAFLD intervention due to its strong antioxidant properties and multi-target regulatory capabilities. Specific mechanisms include:

(1) Scavenging Free Radicals and Inhibiting Oxidative Stress Cascade

The catechol group in hydroxytyrosol directly captures ROS (e.g., superoxide anion O₂⁻, hydroxyl radical ・OH), reducing hepatic levels of oxidative products like malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE).

It activates the antioxidant defense system by upregulating nuclear factor E2-related factor 2 (Nrf2), promoting synthesis of antioxidant enzymes (superoxide dismutase SOD, glutathione peroxidase GPx, catalase CAT), and enhancing hepatocyte antioxidant capacity. Animal studies show hydroxytyrosol significantly reduces hepatic ROS levels and alleviates oxidative damage in high-fat diet-induced NAFLD model mice.

(2) Regulating Lipid Metabolism and Inhibiting Hepatic Steatosis

Inhibiting lipid synthesis: Hydroxytyrosol downregulates sterol regulatory element-binding protein-1c (SREBP-1c) and downstream genes (fatty acid synthase FAS, acetyl-CoA carboxylase ACC), reducing de novo synthesis of fatty acids and triglycerides. It also inhibits 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) to decrease cholesterol synthesis, preventing excessive lipid deposition in hepatocytes.

Promoting lipid breakdown and transport: By activating peroxisome proliferator-activated receptor α (PPARα), hydroxytyrosol enhances expression of mitochondrial β-oxidation-related genes (e.g., carnitine palmitoyltransferase 1 CPT1) for fatty acid oxidation. It upregulates apolipoprotein B (ApoB) synthesis to accelerate very-low-density lipoprotein (VLDL) assembly and secretion, reducing hepatic triglyceride accumulation. Preclinical studies show hydroxytyrosol reduces hepatic triglyceride content by 20%–40% in NAFLD model animals.

(3) Anti-Inflammation and Anti-Fibrosis to Block Disease Progression

Oxidative stress-driven inflammation is critical for NAFLD progression to non-alcoholic steatohepatitis (NASH). Hydroxytyrosol inhibits nuclear factor κB (NF-κB) pathway activation, reducing release of pro-inflammatory factors (TNF-α, IL-6) and hepatic inflammatory infiltration.

It suppresses hepatic stellate cell (HSC) activation, downregulates transforming growth factor-β1 (TGF-β1) and type I collagen expression, and delays liver fibrosis. In cell experiments, hydroxytyrosol reduces HSC collagen secretion by >30%.

(4) Improving Insulin Sensitivity to Disrupt Metabolic Disorder Origins

Hydroxytyrosol activates the AMP-activated protein kinase (AMPK) pathway to promote glucose uptake and utilization, while inhibiting serine phosphorylation of insulin receptor substrate-1 (IRS-1) to restore insulin signaling. This not only improves systemic glucose metabolism but also indirectly reduces hepatic lipid ectopic deposition—alleviated insulin resistance inhibits hepatic glucose uptake and fatty acid conversion, decreasing lipid synthesis substrates.

III. Experimental and Clinical Evidence: Validation from Mechanisms to Applications

Animal Studies

High-fat diet-fed rats intervened with hydroxytyrosol (50–200 mg/kg/d) showed reduced hepatic fat vacuoles, alleviated inflammatory cell infiltration, and improved liver function indices (ALT, AST) in pathological sections. Molecularly, hepatic SREBP-1c and NF-κB activities were significantly inhibited.

Preliminary Clinical Exploration

A small clinical trial (n=40) in obese NAFLD patients showed that 100 mg daily hydroxytyrosol for 12 weeks reduced serum ALT and γ-GT by 15%–20%, hepatic fat content (MRI-PDFF) by ~12%, and oxidative stress marker 8-OHdG levels. Despite limited sample size, results support hydroxytyrosol’s hepatoprotective effect in human NAFLD.

IV. Prospects: Potential and Challenges of Hydroxytyrosol as an Adjuvant for NAFLD Intervention

Hydroxytyrosol’s multi-target, low-toxicity hepatoprotection offers new strategies for NAFLD prevention and treatment. Compared with traditional hepatoprotective drugs, its natural origin (e.g., olive oil extract) and excellent biosafety provide clinical advantages. However, current limitations include undefined optimal dosage, long-term effects, and synergies with other nutrients, as well as small human study samples requiring larger clinical trials. Future directions may explore formulation optimization (e.g., nano-drug delivery systems) to improve bioavailability, and integrate metabolomics/proteomics to uncover potential targets, facilitating its transformation from functional food ingredient to clinical adjuvant therapy.