Abuse or overuse of alcohol, one of major health issues, leads to alcohol-associated fatty liver disease (ALD), which evolves from simple alcoholic steatosis (fatty liver) through alcoholic steatohepatitis (liver inflammation), fibrosis, and cirrhosis [1]. The worldwide rate of alcohol-attributable cirrhosis death was 7.2 deaths per 100,000 people [2]. The toxic effects of ethanol have been linked to its metabolism in the liver [1]. Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase (ADH), microsomal ethanol-metabolizing system mainly cytochrome P450 2E1 (CYP2E1), and catalase [3,4]. It is well known that catalase is an antioxidant enzyme to decompose hydrogen peroxide (H2O2), which has two steps: 1. A free catalase binds one molecule of H2O2 to form a catalase-H2O2 complex; 2. The catalase-H2O2 complex reacts with a second H2O2 to decompose both the 2H2O2 to 2H2O and O2 [5]. If ethanol is present, the second H2O2 will be replaced by ethanol: while the ethanol is oxidized to acetaldehyde, the H2O2 in the catalase-H2O2 complex is decomposed to H2O [5,6]. Only gradually and continuously generated H2O2 could be used by catalase to oxidize ethanol but the H2O2 in a solution could not [[5], [6], [7]]. Catalase is in peroxisomes, so H2O2 is supposed to be generated locally in peroxisomes. Interestingly, peroxisomal fatty acid β-oxidation generates H2O2 [8,9].

Peroxisomes are classic membranous organelles present in all eukaryotic organisms. Peroxisomes are responsible for about 20 % oxygen consumption in the liver [10]. Like mitochondria, peroxisomes also undergo fatty acid β-oxidation and acyl-CoA oxidase (ACOX) is a rate-limiting enzyme that produces H2O2, which is locally detoxified by catalase [11]. Usually, ACOX1 initiates oxidation of very long straight-chain fatty acids and ACOX2 is for branched-chain fatty acids, the resultant short chain fatty acids are further oxidized in mitochondria [8]. ACOX1 is regulated by peroxisome proliferator-activated receptor α (PPARα) [8,9], and PPARα agonist WY-14,643 has been reported to induce ACOX1, which was not observed in PPARα absent (Pparα −/−) mice. However, unlike ACOX1, ACOX2 is not inducible by PPARα agonists [12].

Phytol is derived from chlorophyll that is produced by almost all photosynthetic organisms. Chlorophyll contains a porphyrin ring and a side phytol chain. Bacteria in the rumen of the ruminant animals can digest plant chlorophyll to release phytol, which is absorbed and further metabolized to phytanic acid by the ruminant animals [13,14]. Humans cannot digest chlorophyll to release free phytol, humans obtain phytanic acid primarily from products of the ruminant animals like dairy products and beef. Phytanic acid has 4 side methyl groups with one side methyl group in β-carbon, so β-oxidation is blocked. When phytanic acid is subjected to α-oxidation to remove α-carbon, it is transformed to pristanic acid that there is no side methyl group in β-carbon to block β-oxidation [14]. In rats, pristanic acid is mainly oxidized by pristanoyl-CoA oxidase, also known as ACOX3, but in humans and mice, ACOX2 is the enzyme for pristanic acid oxidation [15]. Currently, phytol is primarily used as a fragrance constituent, but its significant biological properties have recently drawn attention. Recent investigations demonstrated metabolism-modulating, antioxidant, autophagy- and apoptosis-inducing, anti-inflammatory, immune-modulating, and antimicrobial effects [16]. Here, we report that phytol enhanced ethanol metabolism independent of PPARα, but phytol protected against alcoholic steatosis in a PPARα-dependent way.