Natural Product Skatole Ameliorates Lipotoxicity-Induced Multiple Hepatic Damage under Hyperlipidemic Conditions in Hepatocytes

Abstract

Skatole (3-methylindole, 3MI) is a natural-origin compound derived from plants, insects, and microbial metabolites in human intestines. Skatole has an anti-lipid peroxidation effect and is a biomarker for several diseases. However, its effect on hepatocyte lipid metabolism and lipotoxicity has not been elucidated. Hepatic lipotoxicity is induced by excess saturated free fatty acids in hyperlipidemia, which directly damages the hepatocytes. Lipotoxicity is involved in several metabolic diseases and hepatocytes, particularly affecting nonalcoholic fatty liver disease (NAFLD) progression. NAFLD is caused by the accumulation of fat by excessive free fatty acids (FFAs) in the blood and is accompanied by hepatic damage, such as endoplasmic reticulum (ER) stress, abnormal glucose and insulin metabolism, oxidative stress, and lipoapoptosis with lipid accumulation. Hepatic lipotoxicity causes multiple hepatic damages in NAFLD and has a directly effect on the progression from NAFLD to nonalcoholic steatohepatitis (NASH). This study confirmed that the natural compound skatole improves various damages to hepatocytes caused by lipotoxicity in hyperlipidemic conditions. To induce lipotoxicity, we exposed HepG2, SNU-449, and Huh7 cells to palmitic acid, a saturated fatty acid, and confirmed the protective effect of skatole. Skatole inhibited fat accumulation in the hepatocytes, reduced ER and oxidative stress, and recovered insulin resistance and glucose uptake. Importantly, skatole reduced lipoapoptosis by regulating caspase activity. In conclusion, skatole ameliorated multiple types of hepatocyte damage induced by lipotoxicity in the presence of excess free fatty acids.

Examining the Pathogenesis of MAFLD and the Medicinal Properties of Natural Products from a Metabolic Perspective

“…Coniferaldehyde can also reverse impaired glucose uptake caused by high-fat diets by upregulating GLUT2 expression [292]. Skatole, a natural compound produced by plants and intestinal microbes, improved glucose uptake and insulin resistance in HepG2 cells induced by lipotoxicity [293].…”

Microbial-Derived Tryptophan Metabolites and Their Role in Neurological Disease: Anthranilic Acid and Anthranilic Acid Derivatives

“…This study did not test the directionality of skatole levels and so did not postulate whether skatole was a causative agent of disease or a byproduct [ 172 ]. Skatole may be toxic at high concentrations in the body, but a recent study showed skatole may attenuate hyperlipidemic conditions of the liver [ 173 ]. Trp metabolites produced by microbes in the gut, like skatole and tryptamine, find their way to the liver through hepatic circulation and once localized, can either attenuate or exacerbate disease conditions.…”

Artichoke (Cynara scolymus L.) water extract alleviates palmitate-induced insulin resistance in HepG2 hepatocytes via the activation of IRS1/PI3K/AKT/FoxO1 and GSK-3β signaling pathway

“…Numerous studies have shown that palmitic acid (PA), the most abundant saturated FFA in circulation, triggers excessive reactive oxygen species production due to disrupting mitochondrial function and inducing oxidative stress, which has been implicated in the pathogenesis of IR associated with the endoplasmic reticulum (ER) stress [4]. In addition, ER stress and the subsequent unfolded protein response (UPR) also have been implicated in the impaired insulin signaling in hepatocytes caused by PA [5][6][7].…”