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

• Published in: Nutrients Vol. 15; no. 6; p. 1490
• Main Authors: Hong, Sin-Hyoung, Hong, Yeonhee, Lee, Minji, Keum, Byeong-Rak, Kim, Gun-Hwa
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.03.2023; MDPI
• Subjects: Accumulation; Apoptosis; Care and treatment; Caspase; Complications and side effects; Cytotoxicity; Development and progression; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Fatty Acids - metabolism; Fatty Acids, Nonesterified - metabolism; Fatty liver; Glucose; Glucose metabolism; Health aspects; hepatic damage; Hepatocytes; Humans; Hyperlipidemia; Indole; Insulin; Insulin resistance; Intestine; Kinases; Lipid metabolism; Lipid peroxidation; Lipids; lipoapoptosis; lipotoxicity; Liver - metabolism; Liver diseases; Metabolic disorders; Metabolites; Microorganisms; Natural products; Non-alcoholic Fatty Liver Disease - metabolism; nonalcoholic fatty liver disease; Oxidation resistance; Oxidative metabolism; Oxidative stress; Palmitic acid; Peroxidation; Physiological aspects; Phytochemicals; Proteins; Risk factors; skatole; Skatole - adverse effects; Skatole - metabolism; Tumor necrosis factor-TNF; South Korea; United States > US; hepatic damage; natural products; lipoapoptosis; nonalcoholic fatty liver disease; lipotoxicity; lipid accumulation; skatole; endoplasmic reticulum stress; oxidative stress
• ISSN: 2072-6643; 2072-6643
• DOI: 10.3390/nu15061490

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.