Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Abstract

Fatty liver can be diet, endocrine, drug, virus or genetically induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator-activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic and ketogenic genes, promoting hyperglycemia, hyperlipidemia and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency and elevated sympathetic tone. These endocrine and metabolic changes further encourage hepatic steatosis by regulating adipose tissue lipolysis, liver lipid uptake, de novo lipogenesis (DNL), beta-oxidation, ketogenesis and lipid export. Hepatic lipid accumulation may be induced by 4 separate mechanisms: (1) increased hepatic uptake of circulating fatty acids, (2) increased hepatic de novo fatty acid synthesis, (3) decreased hepatic beta-oxidation and (4) decreased hepatic lipid export. This review will discuss the hormonal regulation of each mechanism comparing multiple physiological models of hepatic lipid accumulation. Nonalcoholic fatty liver disease (NAFLD) is typified by increased hepatic lipid uptake, synthesis, oxidation and export. Chronic hepatic lipid signaling through PPARgamma results in gene expression changes that allow concurrent activity of DNL and beta-oxidation. The importance of hepatic steatosis in driving systemic metabolic dysfunction is highlighted by the common endocrine and metabolic disturbances across many conditions that result in fatty liver. Understanding the mechanisms underlying the metabolic dysfunction that develops as a consequence of hepatic lipid accumulation is critical to identifying points of intervention in this increasingly prevalent disease state.

Adipocyte JAK2 mediates aging-associated metabolic liver disease and progression to hepatocellular carcinoma

“…Insulin suppresses gluconeogenesis and induces DNL in liver (9). Thus, the predicted consequence of IR is increased glucose production and reduced lipogenesis.…”

Nonalcoholic Fatty Liver Disease in Children

“…In addition, a high-carbohydrate diet, particularly one that contains high levels of dietary fructose, can increase hepatic DNL by increasing substrate supply and promoting the expression of SREBP-1c and ChREBP. 64,65 DNL is an energy-expensive process consuming 7 ATPs and 14 NADPH to generate each palmitate from acetyl-CoA. 66 Consistent with this, fructose causes hepatic ATP depletion with resultant oxidative stress and potential for mitochondrial dysfunction.…”

Hepatic functional and pathological changes of type 1 diabetic mice in growing and maturation time

“…The liver is a vitally important metabolic organ that regulates glucose and lipid metabolism. 1,2 Liver diseases in diabetic patients have been extensively researched and described earlier, but mainly in T2D cases 3,4 whereas few have been conducted in T1D cases, especially in cases of childhood onset. Therefore, it is meaningful to examine in deeper details the liver damage caused in congenital mice model.…”