Nobiletin Protects Against Alcoholic Liver Disease in Mice via the BMAL1‐AKT‐Lipogenesis Pathway

Jun 8, 2024Molecular nutrition & food research

Nobiletin helps prevent alcohol-related liver damage in mice through a pathway controlling fat production

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Abstract

Nobiletin reduces liver injury and lipid accumulation associated with alcoholic liver disease in Bmal1 mice.

Chronic ethanol feeding leads to liver injury, glucose intolerance, and lipid deposition in mice with normal Bmal1 expression.
Nobiletin significantly mitigates these effects in Bmal1 mice by lowering liver injury markers such as alanine aminotransferase (ALT) and triglycerides.
Nobiletin's protective effects are not observed in Bmal1 liver-specific knockout mice, indicating a dependence on Bmal1.
Ethanol increases the expression of genes related to fat production and promotes cell death in Bmal1 mice.
Nobiletin counteracts ethanol-induced changes in gene expression involved in fat metabolism and apoptosis in a Bmal1-dependent manner.
Nobiletin enhances AKT phosphorylation and alters levels of key proteins involved in fat metabolism in Bmal1 mice.

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SCOPE: Alcoholic liver disease (ALD) is a global public health concern. Nobiletin, a polymethoxyflavone abundant in citrus fruits, enhances circadian rhythms and ameliorates diet-induced hepatic steatosis, but its influences on ALD are unknown. This study investigates the role of brain and muscle Arnt-like protein-1 (Bmal1), a key regulator of the circadian clock, in nobiletin-alleviated ALD.

METHODS AND RESULTS: This study uses chronic ethanol feeding plus an ethanol binge to establish ALD models in Bmal1and Bmal1 liver-specific knockout (Bmal1LKO) mice. Nobiletin mitigates ethanol-induced liver injury (alanine aminotransferase [ALT]), glucose intolerance, hepatic apoptosis, and lipid deposition (triglyceride [TG], total cholesterol [TC]) in Bmal1mice. Nobiletin fails to modulated liver injury (ALT, aspartate aminotransferase [AST]), apoptosis, and TG accumulation in Bmal1LKO mice. The expression of lipogenic genes (acetyl-CoA carboxylase alpha [Acaca], fatty acid synthase [Fasn]) and fatty acid oxidative genes (carnitine pamitoyltransferase [Cpt1a], cytochrome P450, family 4, subfamily a, polypeptide 10 [Cyp4a10], and cytochrome P450, family4, subfamily a, polypeptide 14 [Cyp4a14]) is inhibited, and the expression of proapoptotic genes (Bcl2 inteacting mediator of cell death [Bim]) is enhanced by ethanol in Bmal1mice. Nobiletin antagonizes the expression of these genes in Bmal1mice and not in Bmal1LKO mice. Nobiletin activates protein kinase B (PKB, also known as AKT) phosphorylation, increases the levels of the carbohydrate response element binding protein (ChREBP), ACC1, and FASN, and reduces the level of sterol-regulatory element binding protein 1 (SREBP1) and phosphorylation of ACC1 in a Bmal1-dependent manner. flox/flox flox/flox flox/flox flox/flox

CONCLUSION: Nobiletin alleviates ALD by increasing the expression of genes involved in fatty acid oxidation by increasing AKT phosphorylation and lipogenesis in a Bmal1-dependent manner.

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Nobiletin Protects Against Alcoholic Liver Disease in Mice via the BMAL1‐AKT‐Lipogenesis Pathway

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