Food-Derived β-Carboline Alkaloids Ameliorate Lipid Droplet Accumulation in Human Hepatocytes

Abstract

Lipid droplet accumulation (LDA) in hepatocytes is the initial stage of nonalcoholic fatty liver disease (NAFLD). In the search for natural compounds for the prevention of NAFLD, a series of β-carboline alkaloid derivatives, inspired by flazin and its derivative, newly identified in Crassostrea gigas Thunberg. extracts, were examined for LDA inhibition (LDAI) activity in oleic acid–loaded hepatocytes (HepG2). Eight compounds with a piperidine or pyridine C-ring were chemically synthesized (1–8). Among them, compounds 2 and 4 (flazin) with a carboxy group at C-3 and furfuryl alcohol moiety at C-1 showed low cytotoxicity and they exhibited significant LDAI activity. Compound 2 with piperidine C-ring was identified for the first time in C. gigas extract, and ameliorated the lipid accumulation with the LDAI value of 25.4%. Active compounds 2 and 4 significantly inhibited triacylglycerol species accumulation in cells. These compounds upregulated ATGL and downregulated SREBP1, FASN, and SCD1 genes, suggesting that they activated lipolysis and suppressed lipogenesis, respectively. These results suggest that β-carboline alkaloids, especially compounds 2 and 4, might be potentially useful for preventing NAFLD.

Formation, Identification, and Occurrence of the Furan-Containing β-Carboline Flazin Derived from l-Tryptophan and Carbohydrates

“…In addition, the consumption of natural products might enhance the ingested flazin. Flazin has been previously identified in extracts of Nitraria tangutorum fruit, the seeds of Brucea javanica, and Crassostrea oysters. , Flazin in those products might have been formed by a reaction of carbohydrates (3-deoxyglucosone) with l -Trp, as shown here.…”

“…Flazin was also an inducer of the QR enzyme at micromolar concentrations and showed antioxidant effects in vitro at micromolar levels through the activation of the Keap1-Nrf2 system, resulting in cytoprotection . It inhibited glycation, ameliorated lipid droplet accumulation, and showed immunomodulatory and anticarcinogenic effects. , Therefore, the furan-βCs are bioactive compounds, but additional research is needed to clarify their actions. The widespread presence of flazin in foods, as shown here, suggests that it will be daily ingested, and potentially, it could exert bioactive actions in the body.…”

“…37 Flazin is a promising activator of Keap1-Nrf2 involved in antioxidant protection at 250−500 μM levels in vitro, 38 and it is an active compound against lipid droplet accumulation in hepatocytes. 39 However, very little is known about the significance, formation, and presence of these furan βCs in foods. In a recent study, we have reported the presence and formation of perlolyrine in foods.…”

“…Perlolyrine is an antiproliferative agent against tumor cells in vitro at micromolar levels . Flazin is a promising activator of Keap1-Nrf2 involved in antioxidant protection at 250–500 μM levels in vitro, and it is an active compound against lipid droplet accumulation in hepatocytes . However, very little is known about the significance, formation, and presence of these furan βCs in foods.…”

Inhibition of Lipid Accumulation and Oxidation in Hepatocytes by Bioactive Bean Extracts

“…In addition, the major fatty acids present in the human body are palmitic and oleic acids, and these free fatty acids are easily converted to neutral lipid triacylglycerol (TAG) and their oxidized species, namely, triacylglycerol hydroperoxide (TGOOH). Therefore, understanding their roles in intracellular uptake and cytotoxicity is crucial to understanding the mechanisms of MASH [12]. An increasing number of studies have reported an association between excessive intracellular lipid droplet accumulation (LDA) and obesity, diabetes, and other metabolic disorders [13,14].…”