Lipids and the Liver

The obesity epidemic in Western society has ushered in a new era in hepatology with nonalcoholic fatty liver disease (NAFLD) and its complications occupying center stage. The ineffectiveness of potentially curative therapeutic life style changes has motivated intensive and diverse research efforts to identify pharmacotherapies. In this issue of Seminars, the authors of eight articles highlight key research areas in which substantial progress has been made toward understanding the pathogenesis of NAFLD and identifying new therapeutic opportunities for its management.

The main driver of NAFLD is overnutrition leading to insulin resistance. As enumerated by Xu, So, Park, and Lee, the liver expresses two key transcription factors that promote lipogenesis. Sterol regulatory element binding protein-1c (SREBP-1c) drives the expression of enzymes that synthesize fatty acids and triglycerides in the liver. It is activated by insulin, even in the setting of insulin resistance when high circulating insulin levels fail to suppress hepatic gluconeogenesis. The carbohydrate response element binding protein (ChREPB) is a separate liver-enriched transcription factor that responds directly to glucose and upregulates many of the same lipogenic enzymes. In the setting of hyperinsulinemia and hyperglycemia, the transcriptional activities of these two nutrient-sensing proteins combine to promote lipid accumulation, suggesting they could be targeted in the management of NAFLD.

NAFLD is characterized by the accumulation of excess insoluble triglycerides in hepatocytes, which accumulate in lipid droplets. Once thought to be inert cytoplasmic structures, it is now clear that lipid droplets are dynamic organelles with an array of associated proteins that maintain structure, but also participate in the trafficking of triglycerides within the liver. Goh and Silver review our current understanding of hepatic lipid droplet metabolism, their role in lipoprotein assembly, and potential therapeutic opportunities for NAFLD.

The endoplasmic reticulum (ER) of the hepatocyte is also a key organelle in the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH). In the setting of ER stress, the unfolded protein response (UPR) is activated. Under conditions of obesity and insulin resistance, this is attributable at least in part to the accumulation of saturated free fatty acids. The UPR comprises three molecular pathways that are designed to restore the ER to normal function, or if this is not possible, to promote apoptosis. Henkel and Green discuss the molecular mechanisms that underlie the association between UPR activation and NAFLD. They identify the inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 (XBP1) pathway of the UPR as a key contributor to excess lipogenesis. They also identify therapeutic targets within the UPR for the treatment of NAFLD.

Bile acids are catabolic products of cholesterol that are biosynthesized in the liver. These detergent-like molecules are secreted into bile, promoting the biliary secretion and solubilization of cholesterol. By functioning as endogenous ligands for specific receptors within the liver and adipose tissue, bile acids are also potent signaling molecules. Fuchs, Claudel, and Trauner review the current understanding of mechanisms whereby bile acid-mediated activation of farnesoid X receptor (FXR) and the G-protein coupled receptor TGR5 triggers downstream signaling pathways that control not only bile acid synthesis but also hepatic lipid, glucose, and energy homeostasis. These pathways may be altered and contribute to NAFLD pathogenesis, but also provide attractive molecular targets for therapy.

The increased application of bariatric surgery to the management of obesity-related complications has led to the appreciation that the enteroendocrine system (EES) plays a critical role in the control of hepatic lipid metabolism, which is reviewed by Mells and Anania. Gut peptide hormones from the L-cells of the distal small intestine, including glucagon-like peptide 1 (GLP-1), play key roles in mitigating NAFLD. In response to bariatric surgery, increased delivery of bile acids to the distal small intestine activates TGR5 to increase GLP-1 secretion. This in turn promotes pancreatic insulin secretion, but independently improves fatty acid metabolism in the liver, thereby reducing ER stress. Mellis and Anania also discuss the roles of other major EES peptides in satiety, energy utilization, fat absorption, and intestinal permeability, and offer insights into the therapeutic promise of gut peptides.

The clinical observation that hepatitis C virus (HCV) infection commonly associates with hepatic steatosis and hypocholesterolemia has led to an appreciation of the intimate relationships between the virus and the lipid regulatory machinery of hepatocytes. Schaefer and Chung synthesize the molecular details, pointing out that each step of the viral life cycle is connected to hepatocellular lipid metabolism and trafficking. They describe how HCV replication impacts hepatic cholesterol and triglyceride homeostasis, thereby rationalizing the dyslipidemia that is associated with HCV infection, as well as its response to successful antiviral therapy. Moreover, they explain how viral dependence on hepatic lipid metabolism reveals new molecular targets for the treatment of HCV infection.

The application of modern human genetic analyses has proved fruitful in our understanding of NAFLD. Krawczyk, Portincasa, and Lammert review the role of a common variant in PNPLA3 (synonym = adiponutrin) as a major genetic determinant of hepatic steatosis, as well as the more serious complications of NASH, cirrhosis, and hepatocellular carcinoma. PNPLA3 encodes a lipolytic enzyme of as yet uncertain function that is associated with lipid droplets and regulated by carbohydrates. Children and adults who are homozygous for the p.I148M variant are at increased risk for the serious complications of NAFLD. The distinct and robust effect of this variant has led the authors to propose that the term PNPLA3-associated steatohepatitis (PASH) be included in our vernacular and that genetic testing be introduced into clinical practice to identify NAFLD patients who are increased risk of complications and who might benefit from screening for hepatocellular carcinoma.

The final review addresses the intimate relationship between NAFLD and cardiovascular disease, which represents the most common cause of death in these patients. Much of this risk can be attributed to an atherogenic dyslipidemia that is characterized by increased plasma concentrations of triglycerides, reduced concentrations of high density lipoprotein (HDL) cholesterol, and small dense low-density lipoprotein (LDL) particles. Ed Fisher and I review the structure, function, and metabolism of lipoproteins. We provide a current explanation of how insulin resistance leads to atherogenic dyslipidemia, which underscores the need for careful attention to the management of cardiovascular risk in NAFLD patients.

In each of these articles, the authors have endeavored to provide a clinical/translational perspective on areas of intensive research, which have greatly informed our current understanding of NAFLD. I believe this issue of Seminars will prove valuable to both researchers and clinicians who share interests in improving our management of this common disorder.