Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases

Abstract

NAFLD is closely linked with hepatic insulin resistance. Accumulation of hepatic diacylglycerol activates PKC-ε, impairing insulin receptor activation and insulin-stimulated glycogen synthesis. Peripheral insulin resistance indirectly influences hepatic glucose and lipid metabolism by increasing flux of substrates that promote lipogenesis (glucose and fatty acids) and gluconeogenesis (glycerol and fatty acid-derived acetyl-CoA, an allosteric activator of pyruvate carboxylase). Weight loss with diet or bariatric surgery effectively treats NAFLD, but drugs specifically approved for NAFLD are not available. Some new pharmacological strategies act broadly to alter energy balance or influence pathways that contribute to NAFLD (e.g., agonists for PPAR γ, PPAR α/δ, FXR and analogs for FGF-21, and GLP-1). Others specifically inhibit key enzymes involved in lipid synthesis (e.g., mitochondrial pyruvate carrier, acetyl-CoA carboxylase, stearoyl-CoA desaturase, and monoacyl- and diacyl-glycerol transferases). Finally, a novel class of liver-targeted mitochondrial uncoupling agents increases hepatocellular energy expenditure, reversing the metabolic and hepatic complications of NAFLD.

Keywords: diacylglycerol; insulin resistance; liver metabolism; mitochondria; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; type 2 diabetes.

Figure 1. Insulin action regulates hepatic glucose and lipid metabolism via direct and indirect mechanisms

The liver is exposed to a high concentration of insulin via the portal vein. Binding of insulin to the insulin receptor tyrosine kinase (IRTK) activates Akt2 and acutely activates glycogen synthase. Direct hepatic insulin action will also decrease transcription of gluconeogenic enzymes via inactivation of FOXO1, followed later by a decrease in the protein expression of these enzymes. Insulin signaling also promotes activation and expression of SREBP1. Peripheral insulin action also indirectly impacts hepatic glucose and lipid metabolism. In skeletal muscle, insulin activates glucose transport and glycogen synthesis, limiting glucose as a substrate for hepatic metabolism. In adipose tissue, insulin acts to promote glucose uptake and inhibit lipolysis. The latter decreases fatty acid and glycerol flux. The decrease in fatty acid flux decreases hepatic mitochondrial acetyl-CoA, an allosteric activator of pyruvate carboxylase. The decrease in glycerol flux will also decrease gluconeogenesis by constraining the influx of this substrate. The decrease in fatty acid flux will also decrease esterification of adipose-derived fatty acids.

Figure 2. Mechanisms of hepatic insulin resistance in NAFLD

(1) Skeletal muscle insulin resistance, due to increased intramyocellular ectopic lipid, impairs insulin-stimulated glucose transport activity resulting in reduced muscle glycogen synthesis, redirecting ingested carbohydrate to the liver. (2) The increase delivery of glucose to the liver provides both a substrate for and nutrient activator of (via ChREBP) hepatic de novo lipogenesis. (3) The increases in hepatic DNL and hepatic fatty acid esterification increase hepatic DAG content, activates PKCε, which impairs the direct action of insulin at hepatic IRTK, limiting the ability of insulin to acutely activate glycogen synthesis and, over a longer time period, suppress FOXO1 mediated expression of gluconeogenic enzymes. (4) Adipose insulin resistance from adipose dysfunction and inflammation impairs insulin-mediated suppression of lipolysis increasing glycerol and fatty acid release. These nutrients further impair hepatic glucose metabolism. (5) Fatty acids are esterified into DAG and TAG in an insulin independent manner. (6) Fatty acid oxidation also activates hepatic gluconeogenesis via acetyl-CoA-mediated activation of pyruvate carboxylase (PC), while glycerol delivery to live increases gluconeogenesis via a substrate push mechanism. The net results of these changes are the decrease in insulin-mediated hepatic glycogen synthesis, an increase in hepatic gluconeogenesis and an increase in hepatic lipid synthesis.

Figure 3. Potential targets to treat NAFLD and hepatic insulin resistance

Putative targets to treat NAFLD and hepatic insulin resistance. Some therapeutic pathways (green boxes) broadly regulate metabolic pathways. Other therapeutic targets (purple boxes) are specific enzymes targets in lipid synthetic pathways. While many therapeutic targets indirectly increase energy expenditure, mitochondrial uncouplers (red boxes) directly increase cellular energy expditure decreasing cellular DAG and mitochondrial acetyl CoA which increase insulin signaling and decrease gluconeogenesis. White lines show pathways that have been reported decrease cellular DAG content and/or acetyl CoA concentration. Therapies that improve NAFLD/NASH are labeled with a blue dot. Therapies that improve insulin sensitivyt are labeled with an orange dot. Clinical trials have shown the efficacy of weight loss, bariatric surgery, GLP1 analogs (liraglutide) and PPARγ agonists (rosiglitazone, pioglitozatone). Current clinical investigation has explored the potential for PPARα/δ dual agonists (elafibranor), FXR agonists, FGF21 analogs (LY2405319, PF-052313023) and SCD1 inhibitors (Aramachol). Preclinical studies have shown possible efficacy of dual GLP1/GCGR agonists, intestinal FXR antagonists, inhibitors against MPC (MSDC-0602), ACC1/2 (ND-630), MGAT1 (MOGAT1 ASO), DGAT2 and glucagon-T3 hybrids (not depicted). Preclinical studies have also shown efficacy for liver-targeted mitochondrial uncoupling agents (CRMP) and other agents that increase cellular energy expenditure (e.g. salsalate, TTA, and niclosamide).