Exp Diabetes Res. 2012; 2012: 145754.
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver function tests results, after the commonly investigated causes have been excluded, and frequently coexists with type 2 diabetes mellitus (T2DM) because the conditions have common risk factors. As both T2DM and NAFLD are related to adverse outcomes of the other, diagnosis and valuation of fatty liver is an important part of the management of diabetes. Although noninvasive methods, such as biomarkers, panel markers, and imaging, may support a diagnostic evaluation of NAFLD patients, accurate histopathological findings cannot be achieved without a liver biopsy. As it is important to know whether steatohepatitis and liver fibrosis are present for the management of NAFLD, liver biopsy remains the gold standard for NAFLD diagnosis and evaluation. Therefore, new investigations of the pathogenesis of NAFLD are necessary to develop useful biomarkers that could provide a reliable noninvasive alternative to liver biopsy.

Science. 2011 Jun 24;332(6037):1519-23.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem that affects one-third of adults and an increasing number of children in developed countries. The disease begins with the aberrant accumulation of triglyceride in the liver, which in some individuals elicits an inflammatory response that can progress to cirrhosis and liver cancer. Although NAFLD is strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood, and therapeutic options are limited. Here, we discuss recent mechanistic insights into NAFLD, focusing primarily on those that have emerged from human genetic and metabolic studies.

The disease spectrum of nonalcoholic fatty liver disease. (A) Schematic of progression of NAFLD. The accumulation of TG within lipid droplets in hepatocytes causes steatosis. Steatosis associated with inflammation, cell death, and fibrosis is referred to as NASH, which can progress to cirrhosis. Individuals with cirrhosis have an increased risk of hepatocellular carcinoma. (B) Histological sections illustrating normal liver, steatosis, NASH, and cirrhosis. Collagen fibers are stained blue with Masson’s trichrome stain. The portal triad (PT), which consists of the hepatic artery, portal vein, and bile duct, and the central vein (CV) are shown.

Metabolism of TG in the liver. The three major sources of FFAs are diet, endogenous synthesis, and peripheral tissues. FFAs have four possible fates. They can be metabolized by β oxidation (β-OX) in mitochondria, esterified and stored as TG in lipid droplets, used to form other lipids (not shown), or packaged with apoB into VLDL and secreted into blood. Processes that increase FFA and TG input or reduce FFA and TG output cause hepatic steatosis. Carbohydrate intake increases glucose and insulin levels, which activate two transcription factors in the liver that promote de novo lipogenesis: ChREBP and SREBP-1c. Insulin inhibits lipolysis in adipose tissue by suppressing ATGL. Chylo, chylomicron; TCA, tricarboxylic acid.

Exp. Biol. Med. 2009;234:850-859

Alcoholic fatty liver is a major risk factor for advanced liver injuries such as steatohepatitis, fibrosis, and cirrhosis. While the underlying mechanisms are multiple, the development of alcoholic fatty liver has been attributed to a combined increase in the rate of de novo lipogenesis and a decrease in the rate of fatty acid oxidation in animal liver. Among various transcriptional regulators, the hepatic SIRT1 (sirtuin 1)-AMPK (AMPK-activated kinase) signaling system represents a central target for the action of ethanol in the liver. Adiponectin is one of the adipocyte-derived adipokines with potent lipid-lowering properties. Growing evidence has demonstrated that the development of alcoholic fatty liver is associated with reduced circulating adiponectin levels, decreased hepatic adiponectin receptor expression, and impaired hepatic adiponectin signaling. Adiponectin confers protection against alcoholic fatty liver via modulation of complex hepatic signaling pathways largely controlled by the central regulatory system, SIRT1-AMPK axis. This review aims to integrate the current research findings of ethanol-mediated dysregulation of adiponectin and its receptors and to provide a comprehensive point of view for understanding the role of adiponectin signaling in the development of alcoholic fatty liver.

Figure 1. Proposed mechanisms that underlie the protective action of adiponectin against alcoholic fatty liver. Adiponectin protects against development of alcoholic fatty liver through coordination of multiple signaling pathways mediated by various transcriptional regulators including SIRT1, AMPK, SREBP-1, PGC-1 /PPAR , CD36, and UCP2. Abbreviations: AdipoR, adiponectin receptor; AMPK, AMP-activated kinase; ACC, acetyl-coenzyme A carboxylase; CD36, fatty-acid translocase; FA, free fatty acids; MRC, mitochondrial respiratory chain; SIRT1, sirtuin 1; SREBP-1c, sterol regulatory element-binding protein 1c; PGC-1 , peroxisome proliferator-activated receptor co-activator-alpha; PPAR , peroxisome proliferator-activated receptor alpha; TNF , tumor necrosis factor alpha; UCP2, uncoupling protein-2.

Endocrine Reviews 2008; 29 (7): 939-960

Type 2 diabetes and cardiovascular disease represent a serious threat to the health of the population worldwide. Although overall adiposity and particularly visceral adiposity are established risk factors for these diseases, in the recent years fatty liver emerged as an additional and independent factor. However, the pathophysiology of fat accumulation in the liver and the cross-talk of fatty liver with other tissues involved in metabolism in humans are not fully understood. Here we discuss the mechanisms involved in the pathogenesis of hepatic fat accumulation, particularly the roles of body fat distribution, nutrition, exercise, genetics, and gene-environment interaction. Furthermore, the effects of fatty liver on glucose and lipid metabolism, specifically via induction of subclinical inflammation and secretion of humoral factors, are highlighted. Finally, new aspects regarding the dissociation of fatty liver and insulin resistance are addressed.

I. Introduction

II. Prevalence and Diagnosis of Fatty Liver
A. Prevalence of fatty liver
B. Imaging techniques and histology
C. Laboratory and clinical findings

III. Causes of Fatty Liver
A. Body fat composition, hepatic lipid supply, and adipokines
B. Nutrition
C. Exercise and mitochondrial function
D. Genetics

IV. Metabolic Consequences of Fatty Liver
A. Dyslipidemia
B. Inflammation
C. Insulin resistance
D. Dissociation of fatty liver and insulin resistance

V. Concluding Remarks

Major determinants of fatty liver.

Metabolic consequences of fatty liver. Fat accumulation in the liver induces hyperglycemia, subclinical inflammation dyslipidemia, and the secretion of parameters that can be referred to as “hepatokines” (e.g., fetuin-A), thereby inducing insulin resistance, atherosclerosis, and possibly Beta-cell dysfunction and apoptosis. The degree of these conditions may be moderate [benign fatty liver (left panel)]. However, the same amount of hepatic fat accumulation may, by mechanisms that are yet not fully understood, be strongly associated with hepatic lipotoxicity, resulting in aggravation of hyperglycemia, subclinical inflammation, dyslipidemia, and an imbalance in hepatokine production as well as in their metabolic consequences. This state may be referred to as malign fatty liver (right panel).