Lipotoxicity in steatohepatitis occurs despite an increase in tricarboxylic acid cycle activity

Abstract

The hepatic tricarboxylic acid (TCA) cycle is central to integrating macronutrient metabolism and is closely coupled to cellular respiration, free radical generation, and inflammation. Oxidative flux through the TCA cycle is induced during hepatic insulin resistance, in mice and humans with simple steatosis, reflecting early compensatory remodeling of mitochondrial energetics. We hypothesized that progressive severity of hepatic insulin resistance and the onset of nonalcoholic steatohepatitis (NASH) would impair oxidative flux through the hepatic TCA cycle. Mice (C57/BL6) were fed a high-trans-fat high-fructose diet (TFD) for 8 wk to induce simple steatosis and NASH by 24 wk. In vivo fasting hepatic mitochondrial fluxes were determined by(13)C-nuclear magnetic resonance (NMR)-based isotopomer analysis. Hepatic metabolic intermediates were quantified using mass spectrometry-based targeted metabolomics. Hepatic triglyceride accumulation and insulin resistance preceded alterations in mitochondrial metabolism, since TCA cycle fluxes remained normal during simple steatosis. However, mice with NASH had a twofold induction (P< 0.05) of mitochondrial fluxes (μmol/min) through the TCA cycle (2.6 ± 0.5 vs. 5.4 ± 0.6), anaplerosis (9.1 ± 1.2 vs. 16.9 ± 2.2), and pyruvate cycling (4.9 ± 1.0 vs. 11.1 ± 1.9) compared with their age-matched controls. Induction of the TCA cycle activity during NASH was concurrent with blunted ketogenesis and accumulation of hepatic diacylglycerols (DAGs), ceramides (Cer), and long-chain acylcarnitines, suggesting inefficient oxidation and disposal of excess free fatty acids (FFA). Sustained induction of mitochondrial TCA cycle failed to prevent accretion of "lipotoxic" metabolites in the liver and could hasten inflammation and the metabolic transition to NASH.

Farnesoid X receptor activation induces the degradation of hepatotoxic 1‐deoxysphingolipids in non‐alcoholic fatty liver disease

“…In the setting of obesity, ectopic fat accumulation in the liver seems secondary to chronic free fatty acid overload, together with higher rates of hepatic de novo lipogenesis . Recent evidence suggests that ‘remodelling’ of mitochondrial energetics, morphology, and content play a key role in the pathogenesis of simple steatosis/NASH . Dysfunctional mitochondrial energetics in NAFLD is concurrent to incomplete fat oxidation, leading to accumulation of toxic lipid intermediates, such as diacylglycerols and ceramides, including 1‐deoxysphingolipids.…”

“…Recent evidence suggests that ‘remodelling’ of mitochondrial energetics, morphology, and content play a key role in the pathogenesis of simple steatosis/NASH . Dysfunctional mitochondrial energetics in NAFLD is concurrent to incomplete fat oxidation, leading to accumulation of toxic lipid intermediates, such as diacylglycerols and ceramides, including 1‐deoxysphingolipids. However, alterations in mitochondrial metabolism depend on the ability of hepatocyte to buffer and efficiently metabolize excess toxic lipid intermediates .…”

“…Dysfunctional mitochondrial energetics in NAFLD is concurrent to incomplete fat oxidation, leading to accumulation of toxic lipid intermediates, such as diacylglycerols and ceramides, including 1‐deoxysphingolipids. However, alterations in mitochondrial metabolism depend on the ability of hepatocyte to buffer and efficiently metabolize excess toxic lipid intermediates . In the present study, 1‐deoxySA injection alone in Chow mice did not induce any sign of NAFLD, indicating the ability of healthy liver to efficiently metabolize toxic lipid intermediates (Figure B‐H).…”

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

“…Under conditions of abundant substrate availability (e.g., hepatic lipid accumulation), this uncoupling allows for continued oxidation of fatty acids beyond that required to meet cellular energy requirements (Chavin et al 1999). In fact, despite increased TCA cycle activity, hepatic ATP depletion is a consistent finding in hepatic steatosis (Chavin et al 1999, Koliaki & Roden 2013, Patterson et al 2016. In fatty liver disease, hepatic lipid accumulation, hyperglucagonemia and hypercortisolemia synergistically increase PPARa activity and upregulate gluconeogenic, beta-oxidative and ketogenic gene expression.…”

Treating fatty liver disease by modulating mitochondrial pyruvate metabolism

“…At its core, NAFLD is caused by fat accumulation that is likely driven by nutrient excess. At the same time, the progression to NASH in mice and humans has been tightly linked to a number of factors, including insulin resistance,14, 15 abnormal mitochondrial function,16, 17, 18, 19 oxidative damage, and hepatic inflammation, that promote a state conducive to necropoptosis and replacement of dead hepatocytes with a collagen matrix secreted by hepatic stellate cells in response to these stimuli 20, 21. It is interesting to note that the entire spectrum of this pathophysiology from insulin resistance to fibrotic scarring may involve dysfunctional metabolism driven by overnutrition.…”