Gene-Environmental Interactions as Metabolic Drivers of Nonalcoholic Steatohepatitis

Abstract

Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of chronic liver disease worldwide in the past few decades as a consequence of the global obesity epidemic and is associated with significant morbidity and mortality. NAFLD is closely associated with components of the metabolic syndrome, type 2 diabetes mellitus and cardiovascular disease, suggesting a plausible metabolic mechanistic basis. Metabolic inflexibility is considered a nidus for NAFLD pathogenesis, causing lipotoxicity, mitochondrial dysfunction and cellular stress leading to inflammation, apoptosis and fibrogenesis, thus mediating disease progression into nonalcoholic steatohepatitis (NASH) and ultimately cirrhosis. In this review, we describe they key metabolic drivers that contribute to development of NAFLD and NASH, and we explain how NASH is a metabolic disease. Understanding the metabolic basis of NASH is crucial for the prevention and treatment of this disease.

Keywords: NASH; genes; gut microbiome; inflammation; insulin resistance; lipotoxicity; metabolic syndrome; oxidative stress.

Figure 1

Metabolic Inflexibility. In physiological conditions, fasting state is associated with relatively low insulin levels leading to increased lipolysis and free fatty acid oxidation in adipose tissue and muscles. Glucose oxidation increased in muscles, and gluconeogenesis is activated in the liver. During fed state, food intake increases insulin release which subsequently stimulates lipogenesis and triglyceride accumulation in adipose tissue. There is increase in glucose and free fatty acid oxidation in muscles, and inhibition of gluconeogenesis in the liver. Inability of the body to maintain this balance or to adequately handle substrates at appropriate times is referred to as metabolic inflexibility. The liver loses its ability to flexibly switch back and forth between prandial and fasting states due to exacerbated insulin resistance (hallmark of NAFLD/NASH). Metabolic inflexibility is associated with hyperinsulinemia, systemic lipotoxic cell stress leading to inflammation and fibrogenesis, and eventually NASH. (Adapted from Chakravarthy MV, Siddiqui MS, Forsgren MF and Sanyal AJ (2020), Harnessing Muscle–Liver Crosstalk to Treat Nonalcoholic Steatohepatitis. Front. Endocrinol. 11:592373. doi: 10.3389/fendo.2020.592373.). DNL, de novo lipogenesis; FAO, fatty acid oxidation; FFA, free fatty acid; IR, insulin resistance.

Figure 2

The contribution of mutant PNPLA3 to the risk of NASH and fibrosis. PNPLA3 mutation results in increased oxidative stress and fatty acid oxidation which subsequently leads to accumulation of highly toxic lipid metabolites (e.g. diacylglycerol, ceramides, sphingomyelin, sphingosine). These lipotoxic metabolites trigger immune activation and inflammation via key signaling pathways mediated by p-JNK and p-STAT3, and ultimately activation of several fibrogenic pathways such as those for TGF-β1, α-SMA, Col1 and 3. Col1, collagen I; Col3, collagen III; FA, fatty acid; DAG, diacylglycerol; GSH, GSSG, glutathione-disulfide; glutathione; JNK, c-Jun activated kinase; KDSR, 3-ketodihydrosphingosine reductase; SMA, α-smooth muscle actin; STAT3, signal transducer and activator of transcription, TGF-β, transforming growth factor β.

Figure 3

PNPLA3 ^I148M-associated acceleration of NASH and fibrosis. (A) Liver histology in mouse of empty vector (Luc) after 16 weeks on a Western diet/sugar water (WDSW) diet with NAFLD with minimal fibrosis. (B) Hepatocyte of mouse with PNPLA3 ^I148M after 16 weeks on a WDSW diet demonstrating NAFLD with advanced bridging fibrosis. (A) 16wks AAV LUC (10x) (B) 16wks PNPLA3 I148M (4x).