Hypoxic Signaling and Cholesterol Lipotoxicity in Fatty Liver Disease Progression

Table 1

From triglycerides to toxic lipids: key landmarks representing progress in understanding lipotoxicity in NAFLD.

Year	Landmark	Significance	Ref.
1980	NAFLD characterized for the first time	Liver inflammation detected in Mobridge obesity patients	[27]
1998	The two-hit hypothesis	Inflammation occurs after fat (triglyceride) infiltration of the hepatocytes	[28]
2006	Role of free cholesterol (FC) in NASH described: mitochondrial dysfunction, oxidative damage, and proinflammatory effects	Activation of the immune system, inflammation, and cellular apoptosis, and hepatocyte necrosis	[29]
2007	FC and prooxidant effects recognized	Development of the atherogenic diet model for lipid-induced NASH	[30]
2007	Toxicity of free fatty acids described	Increased fibrosis and protective role of triglycerides	[31]
2008	Lipotoxicity of lysophosphatidylcholine determined	Death signals in hepatocytes induced by lipids	[32]
2010	The multiple-parallel hit hypothesis: NAFLD is a multifactorial disease	(a) Inflammation may precede steatosis or may be activated by failure of antilipotoxic protection; (b) Other parallel hits derived from the gut and/or the adipose tissue may promote liver inflammation via multiple-organ crosstalk; (c) Endoplasmic reticulum (ER) stress and its effect related to signaling networks for steatosis	[33]
2012	Lipids activate NLR family pyrin domain-containing 3 (NLRP3) inflammasomes.	Hepatic long-chain fatty acid composition, a novel determinant in inflammatory response and NASH development	[34]
2012–2014	Ceramide lipotoxicity recognized	Ceramide accumulation and altered acylation pattern in the liver are connected to hepatic steatosis, elevated plasma free fatty acid levels, insulin resistance, and lipotoxicity: these are all noted in NASH	[35, 36]
2017	Cholesterol crystallization within hepatocyte lipid droplets (LDs) observed	Activation of macrophages causes upregulation of tumor necrosis factor (TNF) α, NLRP3, and interleukin 1β. Cholesterol crystals formed on the LD membrane of degrading hepatocytes facilitate inflammatory activation of Kupffer cells	[37]