image: The raw material for de novo fatty acid synthesis is acetyl-CoA, which can be obtained via the citrate shuttle pathway or from acetic acid. ACC and FASN catalyze the conversion of acetyl-CoA into saturated palmitic acid, which can be further modified into other fatty acids by enzymes such as SCD. De novo fatty acid synthesis is promoted by SREBPs. Conversely, the β-oxidation of fatty acids occurs in the mitochondria. Fatty acids are converted into fatty acyl-CoA by ACSL and transported via CPT-1 before being oxidized to acetyl-CoA. Fatty acid β-oxidation is promoted by PPARα. FAs, fatty acids; FASN, fatty acid synthase; SREBP, sterol-regulatory element binding protein; FASN, fatty acid synthase; ACC, acetyl-CoA carboxylase; ACLY, ATP citrate lyase; ACSS, acetyl-CoA synthetase; ACSL, acyl-CoA synthetase; PPAR, peroxisome proliferator-activated receptor; CPT-1, carnitine palmitoyltransferase-1.
Credit: Jun Xing, Kaiguang Zhang, Xiaoxi Feng, Rutong Zhang
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), previously referred to as Non-Alcoholic Fatty Liver Disease (NAFLD), is a prevalent metabolic liver disease. MASLD occurs due to metabolic stress, insulin resistance, and genetic predispositions, contributing to liver fat accumulation unrelated to alcohol consumption or other identifiable liver-damaging factors. With an estimated global prevalence of 29.8%, MASLD significantly burdens public health worldwide, especially in regions with increasing rates of obesity and diabetes. The renaming of NAFLD to MASLD underscores the centrality of metabolic dysfunction in its pathogenesis. MASLD includes a spectrum ranging from simple steatosis to more severe forms, such as Metabolic Dysfunction-Associated Steatohepatitis (MASH), which can further progress to cirrhosis and hepatocellular carcinoma (HCC).
Lipid Metabolism in MASLD
Lipid metabolism plays a crucial role in the development and progression of MASLD, as the liver is central to fatty acid and cholesterol homeostasis. The balance between lipid uptake, synthesis, and degradation in hepatocytes determines the extent of fat accumulation in the liver. In MASLD, six primary disturbances are noted: enhanced fatty acid uptake, increased de novo lipogenesis, reduced lipid oxidation, elevated cholesterol uptake, increased cholesterol synthesis, and heightened bile acid production.
- Fatty Acid Uptake: Proteins such as FATP2, FATP5, and CD36 mediate the uptake of fatty acids into hepatocytes. Overexpression of these transport proteins leads to excessive lipid accumulation, exacerbating MASLD. Additionally, the role of caveolin-1 (CAV-1) in MASLD remains debated, with studies showing both protective and detrimental roles in hepatic fat accumulation.
- De Novo Lipogenesis: The enzymes ATP citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and stearoyl CoA desaturase (SCD) are key drivers of fatty acid synthesis in the liver. Sterol regulatory element-binding protein 1 (SREBP1), a transcription factor, regulates these enzymes and is upregulated in MASLD, promoting lipid accumulation in hepatocytes.
- Fatty Acid Oxidation: Peroxisome proliferator-activated receptor alpha (PPARα) plays a vital role in promoting fatty acid oxidation. In MASLD, impaired fatty acid oxidation leads to the accumulation of lipids in hepatocytes. Enzymes such as carnitine palmitoyltransferase-1 (CPT-1) and acyl-CoA synthetase long-chain family member 1 (ACSL1) facilitate β-oxidation, which is reduced in MASLD.
Cholesterol Metabolism and Bile Acid Synthesis
Cholesterol metabolism also significantly contributes to MASLD pathogenesis. The synthesis of cholesterol, primarily regulated by HMG-CoA reductase (HMGCR) and squalene monooxygenase (SM), is elevated in MASLD. These enzymes increase cholesterol accumulation in hepatocytes. Additionally, Niemann–Pick C1-Like 1 (NPC1L1), which mediates cholesterol uptake, is upregulated in MASLD.
Bile acid synthesis, primarily regulated by cholesterol 7 alpha-hydroxylase (CYP7A1) and farnesoid X receptor (FXR), is another critical pathway implicated in MASLD. FXR activation reduces bile acid synthesis and lipid accumulation, providing a potential therapeutic target for MASLD.
Therapeutic Approaches Targeting Lipid Metabolism
Given the pivotal role of lipid metabolism in MASLD, several therapeutic strategies focus on modulating lipid synthesis and degradation. Glucagon-like peptide-1 (GLP-1) agonists, such as semaglutide and liraglutide, have shown promise in reducing liver fat and improving metabolic parameters in MASLD patients. Inhibitors of SREBP, ACLY, ACC, and FASN have been explored as potential treatments for reducing de novo lipogenesis. Additionally, PPAR agonists and FXR agonists have demonstrated efficacy in promoting lipid oxidation and reducing hepatic fat accumulation.
Chinese proprietary medicines (CPMs) have also gained attention for their potential to target lipid metabolism in MASLD. These natural compounds, such as berberine and curcumin, inhibit fatty acid synthesis while promoting lipid oxidation, offering a complementary approach to traditional pharmacological treatments.
Conclusions
MASLD represents a significant global health challenge, with lipid metabolism disorders at the core of its pathogenesis. Understanding the intricate molecular mechanisms governing lipid uptake, synthesis, and degradation is essential for developing effective therapeutic strategies. While significant progress has been made in targeting lipid metabolism for MASLD treatment, ongoing research is needed to develop more effective therapies with fewer side effects. Novel treatments that modulate lipid metabolism, such as GLP-1 agonists, FXR agonists, and CPMs, hold promise for improving patient outcomes in MASLD.
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The study was recently published in the Journal of Clinical and Translational Hepatology.
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
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Journal
Journal of Clinical and Translational Hepatology
Article Title
Mechanism of Metabolic Dysfunction-associated Steatotic Liver Disease: Important role of lipid metabolism
Article Publication Date
3-Sep-2024