The role of fatty acids in the development and progression of nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) has emerged as a serious obesity-related disorder. NAFLD encompasses a wide spectrum of hepatic derangements ranging from a surfeit of fat in the liver (steatosis) to lipid surplus accompanied by fibrosis and cellular death (nonalcoholic steatohepatitis or NASH). The most widely accepted model to explain the progression from simple NAFLD to NASH is the "two-hit hypothesis," wherein fat over accumulation per se is not sufficient to induce the progression to statohepatitis, but renders the liver more susceptible to "second hits" that, once imposed upon the steatotic liver, cause further aberrations that culminate in the development of NASH. However, in light of recent data from our laboratory and elsewhere, we propose that an increased ratio of saturated-to-unsaturated fatty acids delivered to or stored within the liver may, in part, mediate the progression from simple steatosis to NASH. The molecular mechanisms that mediate the effect of saturated fatty acids are unclear, although proinflammatory cytokines, reactive oxygen species, and endoplasmic reticulum stress may all play a role. Collectively, these data suggest that saturated fatty acids may represent an intrinsic second hit to the liver that hastens the development of NASH.

Figure 1

Caspase activity and DNA fragmentation in H4IIE liver cells. A) Caspase-3 activity and DNA fragmentation were measure in liver cells following 6 or 16 hours of exposure to a control media (LG) or a control media supplemented with thapsigargin (Th, positive control), oleate at 500 μM (O500), palmitate at 500 μM (P500), linoleate at 500 μM (L500), or stearate at 500 μM (S500). B) DNA fragmentation was measured in liver cells following 16 hours of exposure to control media (LG) or control media supplemented with the noted concentrations of fatty acids. *, significantly different from LG and O500 or LG and L500 (p<0.05) [34].

Figure 2

Liver triglycerides, saturated fatty acid composition, caspase-3 activity and liver enzymes in dietary models of hepatic steatosis. Rats were fed a high starch (STD), high sucrose (HSD), high polyunsaturated fat (HPUF) or high saturated fat (HSAT) diet for 4 or 24 weeks. A) Liver triglyceride (TG) concentration and the sum of saturated fatty acids in triglycerides (SatTG) and microsomal membranes (SatMem). B) Liver caspase-3 activity and plasma concentrations of alanine aminotransferase (AAT) and aspartate aminotransferase (AST). *, significantly different from STD and HPUF (p<0.05) [33].

Figure 3

A) Schematic diagram depicting major components of the unfolded protein response as described in text. B) Schematic diagram depicting (bold and italics) the components of the UPR that are known to be activated in response to long chain saturated fatty acids.

Figure 4

Schematic diagram depicting disease progression in NAFLD and hypothesized second hits.