Hyperinsulinemia shifted energy supply from glucose to ketone bodies in early nonalcoholic steatohepatitis from high-fat high-sucrose diet induced Bama minipigs

Abstract

The minipig can serve as a good pharmacological model for human subjects. However, the long-term pathogenesis of high-calorie diet-induced metabolic syndromes, including NASH, has not been well described in minipigs. We examined the development of metabolic syndromes in Bama minipigs that were fed a high-fat, high-sucrose diet (HFHSD) for 23 months, by using histology and serum biochemistry and by profiling the gene expression patterns in the livers of HFHSD pigs compared to controls. The pathology findings revealed microvesicular steatosis, iron overload, arachidonic acid synthesis, lipid peroxidation, reduced antioxidant capacity, increased cellular damage, and inflammation in the liver. RNA-seq analysis revealed that 164 genes were differentially expressed between the livers of the HFHSD and control groups. The pathogenesis of early-stage NASH was characterized by hyperinsulinemia and by de novo synthesis of fatty acids and nascent triglycerides, which were deposited as lipid droplets in hepatocytes. Hyperinsulinemia shifted the energy supply from glucose to ketone bodies, and the high ketone body concentration induced the overexpression of cytochrome P450 2E1 (CYP2E1). The iron overload, CYP2E1 and alcohol dehydrogenase 4 overexpression promoted reactive oxygen species (ROS) production, which resulted in arachidonic and linoleic acid peroxidation and, in turn, led to malondialdehyde production and a cellular response to ROS-mediated DNA damage.

Nonalcoholic fatty pancreas disease as an endogenous alcoholic fatty pancreas disease

“…Thereby, in dysbiotic disorders gut concentrations of EE may be even higher than those found after moderate drinking [62][63][64]. In line with this, genomic studies suggest that alcoholmetabolizing enzymes are differentially expressed in livers of NAFLD/ NAFPD patients [28,30,[65][66][67][68]. These up-regulated enzymes can work at 500 to 3000 mM (~23 to 138 g) ethanol concentrations [69].…”

“…In addition, chronic alcohol exposure induces overexpression of FAEE synthase-related genes in the pancreas and liver [152]. Thus, given the evidence that FAEEs are synthesized by individuals not exposed to exogenous ethanol [103,104] and that NAFLD/NAFPD subjects are exposed to high concentrations of EE [26-32, [65][66][67][68], it is unsurprising that FAEEs play a causative role in NAFPD pathogenesis. It is worth mentioning that the pharmacologic blockage of the hydrolysis of FAEEs to free fatty acids prevents pancreatic necrosis [153].…”

“…In turn, high ketone bodies alongside oxidized carbohydrates and iron overload shift ethanol metabolism from low Km ADH1 (that works in the millimolar range) to high Km alcohol-metabolizing enzymes (that work in the molar range) [65,141] such as cytochrome P450 2E1 (CYP2E1), ADH4, and ADH3 [28,30,66,69,126,142,143]. The net result is that large amounts of ethanol may cause organ damage concurrently with negligible BACs (Figure 2) [28,30,[65][66][67][68].…”

“…A plausible explanation is that chronic exposure to ethanol leads to hyperinsulinemia [125], which shifts energy supply from glucose to ketone bodies [65]. In turn, high ketone bodies alongside oxidized carbohydrates and iron overload shift ethanol metabolism from low Km ADH1 (that works in the millimolar range) to high Km alcohol-metabolizing enzymes (that work in the molar range) [65,141] such as cytochrome P450 2E1 (CYP2E1), ADH4, and ADH3 [28,30,66,69,126,142,143].…”

“…Genomic studies demonstrated that all genes involved in oxidative metabolism of ethanol and acetaldehyde are up-regulated in the livers of NAFLD/NASH patients [28,30,65,66,68]. This suggests that the liver and, probably the pancreas, of these patients consistently metabolize high amounts of EE.…”