The unfolded protein response and hepatic lipid metabolism in non alcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease is a major public health burden. Although many features of nonalcoholic fatty liver disease pathogenesis are known, the specific mechanisms and susceptibilities that determine an individual's risk of developing nonalcoholic steatohepatitis versus isolated steatosis are not well delineated. The predominant and defining histologic and imaging characteristic of nonalcoholic fatty liver disease is the accumulation of lipids. Dysregulation of lipid homeostasis in hepatocytes leads to transient generation or accumulation of toxic lipids that result in endoplasmic reticulum (ER) stress with inflammation, hepatocellular damage, and apoptosis. ER stress activates the unfolded protein response (UPR) which is classically viewed as an adaptive pathway to maintain protein folding homeostasis. Recent studies have uncovered the contribution of the UPR sensors in the regulation of hepatic steatosis and in the cellular response to lipotoxic stress. Interestingly, the UPR sensors can be directly activated by toxic lipids, independently of the accumulation of misfolded proteins, termed lipotoxic and proteotoxic stress, respectively. The dual function of the UPR sensors in protein and lipid homeostasis suggests that these two types of stress are interconnected likely due to the central role of the ER in protein folding and trafficking and lipid biosynthesis and trafficking, such that perturbations in either impact the function of the ER and activate the UPR sensors in an effort to restore homeostasis. The precise molecular similarities and differences between proteotoxic and lipotoxic ER stress are beginning to be understood. Herein, we provide an overview of the mechanisms involved in the activation and cross-talk between the UPR sensors, hepatic lipid metabolism, and lipotoxic stress, and discuss the possible therapeutic potential of targeting the UPR in nonalcoholic fatty liver disease.

Keywords: Endoplasmic reticulum stress; Lipotoxicity; Nonalcoholic steatohepatitis; Palmitate; Sphingolipids.

Figure 1.. Proteotoxic and lipotoxic unfolded protein response signaling.

Proteotoxic stress due to the accumulation of misfolded or unfolded proteins activates the three transmembrane ER stress sensors (IRE1α, PERK, ATF6) by releasing them from BiP binding or by direct biding of the unfolded proteins to the luminal domain of the UPR sensors. Lipotoxic ER stress due to increased membrane saturation or sphingolipid accumulation is sensed by the transmembrane domains of the UPR sensors.Activated IRE1α induces splicing of XBP1. Spliced XBP1 transcriptionally upregulates genes that encode protein folding machinery, ERAD genes, and lipid synthesis pathways. PERK phosphorylates eIF2α which suppress mRNA translation leading to attenuation of protein synthesis. ATF4 is selectively translated and upregulates several transcriptional targets including CHOP. CHOP-dependent apoptosis occurs under unresolved ER stress. ATF6α translocates from the ER to the Golgi complex and cleaved by S1P and S2P. Cleaved ATF6α, termed ATF6N, transcriptionally upregulates UPR target genes. Abbreviation: IRE1α, inositol-requiring enzyme 1; PERK, PKR-like endoplasmic reticulum kinase; ATF6α, activating transcription factor 6; TRAF2, Tumor necrosis factor receptor-associated factor 2; ASK1, apoptosis-signal-regulating kinase 1; JNK, c-Jun N-terminal kinase; XBP1u, X-box binding protein 1; XBP1s, spliced X-box binding protein 1; RIDD, regulated IRE1α-dependent decay; eIF2α, eukaryotic translation initiation factor 2α; GADD34, growth arrest and DNA damage-inducible protein; ATF4, activating transcription factor 4; UPR, unfolded protein response; ERAD, endoplasmic reticulum-associated degradation; CHOP, CCAAT-enhancer-binding protein homologous protein; ATF6N, cleaved ATF6; BiP, binding immunoglobulin protein; S1P, site 1 protease; S2P, site 2 protease.

Figure 2.. Palmitate-induced lipotoxicity.

Excess palmitate availability to the hepatocyte, derived predominantly from adipose tissue lipolysis in insulin resistance, leads to lipid accumulation and palmitate lipotoxicity. To maintain lipid homeostasis, fatty acid disposal in the liver occurs through the formation of triglyceride which is then stored temporarily as lipid droplets (steatosis) or secreted as VLDL. In hepatocytes, conversion of free fatty acids to triglycerides protects the cells from lipotoxicity; whereas higher levels of SFAs such as palmitate, are lipotoxic. Palmitate can be directly or indirectly metabolized into other lipid classes including ceramides and LPC which contribute to palmitate-induced ER stress. The generation of lipotoxic metabolites of fatty acids typically occurs in parallel with the accumulation of triglyceride droplets (steatosis), resulting in the hallmark features recognized as nonalcoholic steatohepatitis where steatosis and hepatocellular injury are present together. Abbreviation: SFA, saturated fatty acid; DAG, diacylglycerol; PC, phosphatidylcholine; PLA2, phospholipase A2; LPC, lysophosphatidyl choline; SCD1, stearolyl-CoA desaturase; TG, triglyceride; VLDL, very low density protein; ER, endoplasmic reticulum.