Sodium 4-phenylbutyrate prevents murine dietary steatohepatitis caused by <i>trans</i>-fatty acid plus fructose

Abstract

Excess consumption of trans-fatty acid could increase the risk of non-alcoholic steatohepatitis (NASH); however, treatment targeting trans-fatty acid-induced NASH has not been examined. Here we focused on the influence of trans-fatty acid intake on endoplasmic reticulum (ER) stress in hepatocytes, so we investigated the effect of the chemical chaperone 4-phenylbutyric acid (PBA), on trans-fatty acid-caused steatohepatitis using diabetic KK-Ay mice. Elaidic acid (EA, trans-fatty acid) alone did not cause definitive liver injury. In contrast, EA plus low-dose fructose induced extensive apoptosis in hepatocytes with severe fat accumulation. EA plus fructose significantly increased ER stress markers such as glucose-regulated protein 78 (GRP78), eukaryotic initiation factor 2α (eIF2α) and phosphorylated c-jun N-terminal kinase (JNK), while PBA significantly reduced this response. In vitro, EA promoted expression of GRP78 and phosphorylation of eIF2α in primary-cultured hepatocytes. EA also increased hepatocellular susceptibility to low-dose tert-butyl hydroperoxide. Treatment with PBA significantly reduced these responses. In conclusion, EA potentiates susceptibly to non-hazardous dose of fructose, and increases ER and oxidative stress. PBA improved steatohepatitis induced by EA plus fructose through amelioration of ER stress. Therefore, ER stress-targeted therapy using a chemical chaperone is a promising novel strategy for trans-fatty acid-induced steatohepatitis.

Industrial Trans Fatty Acids Stimulate SREBP2‐Mediated Cholesterogenesis and Promote Non‐Alcoholic Fatty Liver Disease

“…Previously, Koppe and colleagues showed that compared to diets high in saturated fatty acids, a diet high in industrial trans fatty acids markedly increased plasma ALT activity in AKR/J mice, suggesting enhanced liver damage . Furthermore, studies in different mouse strains revealed that diets rich in industrial trans fatty acids promote hepatic steatosis and fibrosis . Our in vivo study, which provides the most detailed characterization of the effects of industrial trans fatty acids on the liver, extends these findings by showing that a diet enriched in trans fatty acids enhances liver steatosis and fibrosis, and raises hepatic triglyceride levels, hepatic cholesterol levels, plasma acute phase proteins, and plasma ALT activity.…”

Orally administered sodium 4‑phenylbutyrate suppresses the development of dextran sulfate sodium‑induced colitis in mice

“…It has been reported that PBA may act as a histone deacetylase inhibitor, serve as a chemical chaperone, or act as an ammonia scavenger (17). Furthermore, PBA has been found to suppress endoplasmic reticulum stress and exert anti-inflammatory effects (18)(19)(20)(21). The authors of the present study have previously reported that PBA may function as a therapeutic reagent for neurodegenerative disorders, and that intraperitoneal administration of PBA suppresses the onset of experimental murine colitis (22,23).…”

“…In the present study, orally administered PBA was demonstrated to delay the onset of experimental colitis. PBA treatment is not accompanied by the particular side effects of existing IBD therapeutics, and has the added benefit of an oral route of administration (15)(16)(17)(18)(19)(20)(21). PBA may therefore be one of a new type of therapeutic agents, which includes anti-TNF-α therapies (29)(30)(31)(32)(33).…”

L‐carnitine prevents metabolic steatohepatitis in obese diabetic KK‐Ay mice

“…For histological evaluation, liver tissues were fixed in 10% buffered formalin and embedded in paraffin, and hematoxylin–eosin staining was carried out. Caspase cleavage product of cytokeratin (ccCK) 18 was detected by immunohistochemistry using M30 CytoDEATH monoclonal antibody (Roche, Basel, Switzerland) as described previously . Briefly, deparaffinized tissue sections were incubated with a monoclonal anti‐M30 antibody and secondary biotinylated anti‐mouse immunoglobulin G, and the specific binding was visualized with avidin–biotin complex solution followed by incubation with a 3, 3‐diaminobenzidine tetrahydrochloride solution using a Vectastain Elite ABC kit (Vector Laboratories, Burlingame, CA, USA).…”