Cholesterol Metabolism in Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) has emerged as a global health challenge, affecting up to a quarter of adults worldwide. A hallmark of NAFLD is the dysregulation of cholesterol metabolism, encompassing dietary absorption, hepatic synthesis, intracellular trafficking and conversion to bile acids. Hepatic cholesterol homeostasis is maintained through a network of pathways: the mevalonate cascade that drives de novo synthesis, uptake of cholesterol-rich lipoproteins via the LDL receptor, esterification by acyl-CoA:cholesterol acyltransferase and efflux through bile acid formation and export. In NAFLD, this balance shifts towards free cholesterol accumulation in hepatocytes, triggering endoplasmic reticulum stress, mitochondrial dysfunction and lipotoxic injury. Excess cholesterol may crystallise within lipid droplets, provoking activation of Kupffer cells and recruitment of inflammatory mediators that drive progression to nonalcoholic steatohepatitis (NASH), fibrosis and ultimately hepatocellular carcinoma. Recent work highlights the interplay between cholesterol overload, lysosomal impairment and disrupted autophagy, unveiling novel targets for intervention. A deeper understanding of these interconnected pathways is critical for therapies that restore cholesterol homeostasis and slow disease progression.

Research from Nature Portfolio

Recent studies have illuminated the profound impact of dietary cholesterol and metabolic signatures in NAFLD. Metabolomic profiling in non-obese mouse models defined a distinct lipidome driven by elevated free cholesterol, cholesterol esters and cholic acid, uncovering alterations in sphingolipid and phosphatidylcholine metabolism that predispose to steatohepatitis independent of obesity. Complementary genetic and expression analyses in high-cholesterol-fed mice revealed that chronic dietary cholesterol accelerates the transition from simple steatosis to steatohepatitis and hepatocellular carcinoma. Dysregulated calcium signalling and aberrant activation of metabolic and cell-adhesion pathways underpin this malignant progression, providing a framework for future therapeutic targeting.

Cholesterol Metabolism in Nonalcoholic Fatty Liver Disease publication trend

The graph below shows the total number of articles in cholesterol metabolism in nonalcoholic fatty liver disease across all publications each year (not limited to Nature Index journals).

Technical terms

Free cholesterol (FC): non-esterified cholesterol that can accumulate in cell membranes and organelles, leading to lipotoxicity.

Cholesterol esters (CE): storage form of cholesterol formed by esterification with fatty acids and deposited in lipid droplets.

Lipophagy: selective autophagic degradation of lipid droplets, crucial for cholesterol and triglyceride clearance.

Kupffer cells: resident hepatic macrophages that clear debris and mediate inflammatory responses in the liver.

Steatohepatitis (NASH): progressive stage of fatty liver disease characterised by inflammation, hepatocyte injury and fibrosis.

PPARα: nuclear receptor that regulates genes controlling fatty acid oxidation and cholesterol catabolism.

References

1. Free Cholesterol‐Induced Liver Injury in Non‐Alcoholic Fatty Liver Disease: Mechanisms and a Therapeutic Intervention Using Dihydrotanshinone I. Advanced Science (2024).
2. Lysosomal cholesterol overload in macrophages promotes liver fibrosis in a mouse model of NASH. Journal of Experimental Medicine (2023).
3. Complementary gene regulation by NRF1 and NRF2 protects against hepatic cholesterol overload. Cell Reports (2023).
4. Dietary cholesterol promotes steatohepatitis related hepatocellular carcinoma through dysregulated metabolism and calcium signaling. Nature Communications (2018).
5. Metabolomic characteristics of cholesterol-induced non-obese nonalcoholic fatty liver disease in mice. Scientific Reports (2017).
6. Cholesterol crystallization within hepatocyte lipid droplets and its role in murine NASH[S]. Journal of Lipid Research (2017).
7. Disturbances in Cholesterol Homeostasis and Non-alcoholic Fatty Liver Diseases. Frontiers in Medicine (2020).