Highlights

  • Berberine reverses liver triglyceride elevations and lowers enzyme markers for liver disease (alanine transaminase [ALT] and aspartate transaminase [AST]) in a high fat diet-induced liver disease mouse model.
  • Lower levels of the pro-longevity protein sirtuin 1 (SIRT1) were found in liver disease patients, yet berberine increased SIRT1 levels in the liver disease mouse model.
  • SIRT1 improves the functional stability of a protein called CPT1A that functions to metabolize cell fats and thereby increases liver cell fat metabolism.


About 29.8% of adults have a condition where fat builds up in the liver called non-alcoholic fatty liver disease (NAFLD) globally, and the disease has an astonishing 35.7% prevalence in North America. With time, NAFLD can progress to cirrhosis, a degenerative disease encompassing liver scarring and progressive failure, or even liver cancer. Currently, no specific drug has received Food and Drug Administration (FDA) approval targeting NAFLD. With NAFLD’s pervasiveness and considerable health burden, researchers continuously seek molecules to alleviate this condition.

Published in Gastroenterology Report, Wei and colleagues from Sun Yat-sen University in China show that berberine improves liver triglyceride metabolism and lowers enzyme markers for liver damage, namely ALT and AST. Lower levels of the pro-longevity protein SIRT1 were found in patients with NAFLD, yet berberine increased SIRT1 levels in the NAFLD mouse model, suggesting a role for SIRT1 in alleviating NAFLD. Wei and colleagues went on to show that SIRT1 improves the stability and function of a protein with key roles in cellular fat metabolism called CPT1A. In doing so, the elevated SIRT1 from berberine treatment improves CPT1A functioning to drive better liver cell fat metabolism, hence alleviating NAFLD. These findings suggest berberine supplementation can ameliorate NAFLD by increasing SIRT1 to stabilize CPT1A and drive liver cell fat metabolism.

Berberine Increases SIRT1 to Enhance Cellular Fat Metabolism and Alleviate Non-Alcoholic Fatty Liver Disease

To find whether berberine improves NAFLD, Wei and colleagues measured NAFLD model mice liver triglyceride levels. They found about a four-fold triglyceride level increase in NAFLD mice, yet berberine treatments cut these elevated levels in half. These findings suggest berberine improves liver fat metabolism to lower triglyceride levels.

Wei and colleagues sought to find whether berberine-induced lower triglyceride levels result in reduced liver damage. They examined blood levels of enzyme markers for liver damage, ALT and AST. They found about twice the blood ALT and AST levels in high fat diet-fed mice, but berberine nearly reversed the high enzyme levels to those of healthy mice. These results show that berberine treatments improve liver damage in a mouse model for NAFLD.

Berberine decreases triglyceride levels and improves liver enzyme markers in a NAFLD model.
(Wang et al., 2023 | Gastroenterology Report) Berberine lowers triglyceride levels in a NAFLD model and substantially improves enzyme markers for liver damage. B) Mice with high-fat diet-induced NAFLD (HFD+Vehicle) displayed about a four-fold increase in liver triglyceride levels. Berberine treatment (HFD+BBR) almost cut in half the NAFLD-associated high triglyceride levels. F and G) The high-fat diet induced NAFLD mice (HFD+Vehicle) showed dramatically elevated liver damage enzyme markers ALT and AST, but berberine substantially reduced the liver damage markers (HFD+BBR).

The China-based researchers sought a better understanding of how berberine improves NAFLD. They looked at data from patients with liver disease and found they have significantly lowered gene activity for a gene that codes the pro-longevity protein SIRT1. Since lower gene activity ties to lower protein levels, these findings suggest liver disease patients likely have lower SIRT1 levels.

For confirmation of lowered SIRT1 levels in NAFLD and to test berberine’s effects on SIRT1 levels, Wei and colleagues measured SIRT1 levels in NAFLD mice. They found drastically lower SIRT1 levels in the NAFLD mice but that berberine dramatically increased their SIRT1 protein levels. These data suggest that berberine can substantially restore NAFLD-induced SIRT1 deficiencies.

Reduced SIRT1 gene activity in liver disease patients and NAFLD mice, with restoration by berberine.
(Wang et al., 2023 | Gastroenterology Report) Lower SIRT1 gene activity in liver disease patients and NAFLD mice shows lower SIRT1 in liver disease, yet berberine restores SIRT1 levels. A) In two groups of liver disease patients, steatosis (a condition marked by fat building up in the liver) and non-alcoholic steatohepatitis (NASH [a fatty liver disease characterized by inflammation]), SIRT1 activity measured with RNA levels was significantly lower than healthy adults. D) Mice with high-fat diet-induced NAFLD (HFD+Vehicle) showed significantly lower SIRT1 protein levels than healthy mice (Chow+Vehicle), but berberine (HFD+BBR) dramatically increased SIRT1 levels.

To get a better grasp on how improved SIRT1 levels improve NAFLD, Wei and colleagues measured how SIRT1 affects a protein that stimulates cellular fat metabolism — CPT1A. They used human liver cells immersed in palmitate, a cellular fat, to mimic cell NAFLD conditions. In these cells, they measured the effects of inhibiting SIRT1 and found that CPT1A levels significantly fell without SIRT1. To find how important CPT1A is to cellular fat metabolism, they measured CPT1A’s influence on cellular fat metabolism — a process called fatty acid oxidation. By genetically blocking CPT1A expression, fatty acid oxidation substantially declined, but the reintroduction of CPT1A restored it. What’s more, with higher concentrations of berberine, fatty acid oxidation increased. These findings suggest that SIRT1 is necessary to maintain CPT1A activity and that CPT1A drives fatty acid oxidation to reduce cell fats like triglycerides. Berberine stimulates this process since higher berberine concentrations triggered greater fatty acid oxidation activity.

Correlation between SIRT1 and CPT1A levels in cellular fat metabolism. E) Inhibited SIRT1 in human liver cells (shSIRT1; blue line) leads to decreased CPT1A protein levels over six hours. H) Liver cells with ablated CPT1A (CPT1A KO; blue bar) exhibit lower cellular fat metabolism and fatty acid oxidation. Reintroduction of CPT1A (r-CPT1A; red bar) increases fatty acid oxidation. I) Berberine-treated liver cells at higher concentrations (10 µM and 20 µM) demonstrate increased fatty acid oxidation activity.
(Wang et al., 2023 | Gastroenterology Report) Higher SIRT1 levels are tied to increased CPT1A levels, a protein that drives cellular fat metabolism, suggesting higher SIRT1 drives CPT1A function. E) Human liver cells with genetically inhibited SIRT1 (shSIRT1; blue line) exhibit falling CPT1A protein levels for up to six hours. H) Liver cells with genetically ablated CPT1A (CPT1A KO; blue bar) show significantly lower cellular fat metabolism, fatty acid oxidation. Reintroducing CPT1A (r-CPT1A; red bar) substantially increases fatty acid oxidation. I) Liver cells treated with higher concentrations of berberine (10 µM and 20 µM) display significantly higher fatty acid oxidation activity.

“Our study revealed a new mechanism of berberine in the treatment of NAFLD,” said Wei and colleagues.

Increasing SIRT1 to Fight Non-Alcoholic Fatty Liver Disease

The study showed that berberine improves liver triglyceride metabolism in a mouse model for NAFLD. Berberine also improved enzyme markers for liver damage, suggesting the improved triglyceride metabolism lowered liver damage from NAFLD.

To find how berberine improves liver health, Wei and colleagues showed berberine increases liver SIRT1 levels. The protein CPT1A that functions to increase liver cell fat metabolism through fatty acid oxidation depends on SIRT1 to increase fat metabolism. These findings show that berberine improves NAFLD in a SIRT-1-dependent manner.

Other SIRT-1 activators which may increase SIRT1 levels include resveratrol, quercetin, curcumin, and fisetin. Resveratrol has been shown to exert positive effects on blood fat profiles and acts as an antioxidant. Quercetin and curcumin have anti-inflammatory effects and improve blood fat profiles. Fisetin has anti-inflammatory properties and has been shown to prevent cardiovascular complications. Evidence suggests that these SIRT-1 activators could improve NAFLD by increasing SIRT1 levels and activity.

A mouse study found that quercetin improves NAFLD but didn’t specify whether it did so via SIRT1, and another mouse study showed that curcumin also improves NAFLD. Yet another mouse study showed that fisetin improves liver health in alcohol-induced liver injury by increasing SIRT1 activation, and the possibility remains that it may have similar effects in NAFLD. Liver disease studies with resveratrol show mixed results. These data suggest that stimulating SIRT1 could be a promising way to improve NAFLD. Future studies and developments could bring about new SIRT1 activators to improve liver health.