Pathogenesis and Prevention of Hepatic Steatosis

Abstract

Hepatic steatosis is defined as intrahepatic fat of at least 5% of liver weight. Simple accumulation of triacylglycerols in the liver could be hepatoprotective; however, prolonged hepatic lipid storage may lead to liver metabolic dysfunction, inflammation, and advanced forms of nonalcoholic fatty liver disease. Nonalcoholic hepatic steatosis is associated with obesity, type 2 diabetes, and dyslipidemia. Several mechanisms are involved in the accumulation of intrahepatic fat, including increased flux of fatty acids to the liver, increased de novo lipogenesis, and/or reduced clearance through β-oxidation or very-low-density lipoprotein secretion. This article summarizes the mechanisms involved in the accumulation of triacylglycerols in the liver, the clinical implications, and the prevention of hepatic steatosis, with a focus on the role of mitochondrial function and lifestyle modifications.

Keywords: Mitochondria; diet; exercise; fatty acids; fatty liver; hepatic steatosis; mitochondrial trifunctional protein; triacylglycerol; β-oxidation.

Figure 1

The pathogenesis of hepatic steatosis. Under physiologic conditions, the hepatic fatty acid (FA) pool is the result of a balance between FA influx from the diet and adipose tissue lipolysis, de novo lipogenesis (DNL), and disposal of FAs through β-oxidation or very-low-density lipoprotein (VLDL) assembly and secretion. Increased uptake and reduced clearance of FAs lead to the accumulation of lipid droplets (LDs) and hepatic steatosis. In red are some important proteins involved in the different pathways. ApoB, apolipoprotein B; CD36, fatty acid translocase; ChREBP, carbohydrate-responsive element—binding protein; CMs, chylomicrons; FATP, fatty acid transport protein; FFAs, free fatty acids; MTP, mitochondrial trifunctional protein; MTTP, microsomal triglyceride transfer protein; SREBP-1c, sterol regulatory element—binding protein 1c; TAG, triacylglycerol.

Figure 2

Mitochondrial fatty acid oxidation. Short- and medium-chain fatty acids (SCFAs/MCFAs) traverse the plasma membrane passively while long-chain fatty acids (LCFAs) require membrane transporters (fatty acid translocase [CD36] and fatty acid transport protein 5 [FATP5]). LCFAs are acylated in the cytosol and then enter the mitochondria, helped by the carnitine acyl-transferases (carnitine palmitoyltransferases) CPT1 and CPT2. The β-oxidation of acyl-coenzyme A (acyl-CoA) takes place in the mitochondria and consists of 4 reactions, with the last 3 catalyzed by the mitochondrial trifunctional protein. β-Oxidation spiral leads to the formation of acetyl-CoA, nicotinamide adenine dinucleotide (NADH), and flavin adenine dinucleotide (FADH₂) from each oxidation cycle. NADH and FADH₂ are used by the mitochondrial respiratory chain to generate adenosine triphosphate.