Fatty Acid Elongation in Non-Alcoholic Steatohepatitis and Hepatocellular Carcinoma

Abstract

Non-alcoholic steatohepatitis (NASH) represents a risk factor for the development of hepatocellular carcinoma (HCC) and is characterized by quantitative and qualitative changes in hepatic lipids. Since elongation of fatty acids from C16 to C18 has recently been reported to promote both hepatic lipid accumulation and inflammation we aimed to investigate whether a frequently used mouse NASH model reflects this clinically relevant feature and whether C16 to C18 elongation can be observed in HCC development. Feeding mice a methionine and choline deficient diet to model NASH not only increased total hepatic fatty acids and cholesterol, but also distinctly elevated the C18/C16 ratio, which was not changed in a model of simple steatosis (ob/ob mice). Depletion of Kupffer cells abrogated both quantitative and qualitative methionine-and-choline deficient (MCD)-induced alterations in hepatic lipids. Interestingly, mimicking inflammatory events in early hepatocarcinogenesis by diethylnitrosamine-induced carcinogenesis (48 h) increased hepatic lipids and the C18/C16 ratio. Analyses of human liver samples from patients with NASH or NASH-related HCC showed an elevated expression of the elongase ELOVL6, which is responsible for the elongation of C16 fatty acids. Taken together, our findings suggest a detrimental role of an altered fatty acid pattern in the progression of NASH-related liver disease.

Up-regulated HOTAIR induced by fatty acids inhibits PTEN expression and increases triglycerides accumulation in HepG2 cells

“…The present study used FFAs to establish a cell model of human NAFLD. The results showed triglyceride accumulation in HepG2 cells after treatment with FFAs, consistent with previous studies [27][28][29][30].…”

“…When obesity causes triglycerides failure to be stored in the adipose tissue, triglycerides are transformed into FFAs that are transported to nonadipose tissues [26]. Saturated palmitic (PA; C16:0) and monounsaturated oleic (OA; C18:1) acids are the most abundant FFAs in the liver triglycerides of patients with NAFLD [27,28]. Previous studies showed that in vitro NAFLD models induced by FFAs mixture (PA/OA, 1:2 ratio) could lead to triglyceride accumulation in hepatocytes similar to that of patients with NAFLD, with minor toxic and apoptotic effects [29,30].…”

Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

“…The fatty acid composition and the accumulation of free cholesterol have been implicated in playing a critical role in the development of NASH since an altered lipidome [3,11,12] as well as free cholesterol, positively correlate with the severity of NASH [10,12,28,29] . Dietary cholesterol may play a role in NAFLD onset [30] .…”

“…Fatty acid extraction and alkaline hydrolysis was performed using the fatty acid methyl ester method and measured with GC-MS as previously published [3,23] .…”

“…The composition of fatty acids in the liver has emerged as a critical factor promoting the development of non-alcoholic steatohepatitis (NASH) and potentially HCC [3][4][5][6][7] , with monounsaturated fatty acids (MUFA) implicated in a pathophysiological role [6,8] . Recent observations also highlighted the accumulation of free cholesterol as an important trigger for the progression from simple steatosis to severe NASH [9][10][11] .…”