3.3. Lipotoxicity

resistance is also related to oxidative stress, which has the most important role in carcinogen-

Epidemiologic studies show that diabetes is associated with an increased risk of developing HCC compared with non-diabetics patients, regardless of other HCC risk factors and also seems to be independent of obesity [47]. In a large study conducted on patients with and without diabetes, with a follow-up period of 10–15 years, NAFLD incidence was significantly higher among patients with diabetes and a significantly higher incidence of HCC among patients with diabetes was observed [7]. Meta-analysis published over the years, revealed a 2 to 3-fold greater risk of HCC in patients with diabetes compared with non-diabetic patients, and this significant association was reported independent of alcohol abuse or chronic viral

Epidemiologic data demonstrate that both obesity and type 2 diabetes mellitus have increases the risk for HCC, and NAFLD, which is present in up to 90% of obese persons and up to 70% of type 2 diabetes mellitus patients [24], appears to play an important role in HCC development. NAFLD is nowadays considered the most common risk factor for HCC, followed by type 2 diabetes and it is exceeding the incidence of chronic viral infections and alcoholic liver disease [48, 50]. These can be explained by effective measures to reduce HCV infection incidence, which was the major cause of HCC in the United States and in other developed countries,

The strong relationship between visceral obesity and insulin resistance (IR) is well known, but insulin resistance is not related only to adipose tissue, in fact, liver accumulation of fatty acid metabolites can induce hepatic insulin resistance. One of the main fatty acid metabolite involved in hepatic insulin resistance is diacylglycerol (DAG) and it has been proposed as a predictor for hepatic insulin resistance [52]. The consequent hyperinsulinemia downregulates s expression of IRS2 in the hepatic cells increasing hepatic insulin resistance and in addition, insulin stimulates lipogenesis through activation of SREBP-1c, inducing, in a vicious circle with further fat accumulation and insulin resistance [31]. The liver microenvironment may induce insulin resistance also in other tissues, in fact, an increase in liver fat content may be considered a very strong predictor of insulin resistance in skeletal muscles, hepatic and adipose tissue, regardless of adiposity. In conclusion, liver fat content may predict the development of metabolic syndrome or diabetes, and the underlying mechanism may be the altered gene expression and protein synthesis and secretion also observed in NAFLD [53]. It is known that hyperinsulinemia occurs as a response to insulin resistance, and that is considered a risk factor for liver fibrosis and HCC development by activation of hepatic stellate cells, by dysregulation in the proliferation-apoptosis balance in hepatic cells, and by stimulation of angiogenesis. The most studied mechanism involved in NAFLD-related HCC is the IGF signaling axis that has a growth factor-like activity on hepatic cells and also a pro-angiogenic activity on the hepatic vascular system. Dysregulation of the IGF signaling axis has an important role in hepatic carcinogenesis and it is represented by the low levels of IGF1 in serum and overexpression of IGF-II. Insulin receptors (IRS) bind to insulin or IGF and share the same prooncogenic pathways with IGF1 receptor (IGF1R), including the activation of P13K/Akt and

and also can be explained by the increasing prevalence of NAFLD in these areas [51].

esis in the presence of NAFLD and NASH.

102 Liver Cancer

MAPK [54, 55].

hepatitis in studies that examined these factors [48, 49].

Increased lipid accumulation in the liver arises from lipolysis within peripheral adipose tissue, dietary sources and de novo hepatic lipogenesis, and this increased lipid accumulation causes hepatic lipotoxicity resulting in the excessive production of saturated and monounsaturated free fatty acids (FFAs) [40, 46, 56]. These FFAs undergo β-oxidation leading to formation of reactive oxygen species that will further induce mitochondrial damage, endothelial reticulum stress, and gene transcription promoting inflammatory cell signaling pathways.

As a result of the hepatic insulin resistance an increase in the liver of free fatty acids (FFAs) is observed, mainly due to dysregulation of the lipolysis and lipogenesis balance, resulting lipotoxicity that will determine chronic damage to hepatic tissue [51]. But, lipotoxicity is not due only as consequence of the excessive accumulation of FFAs in the liver, and the modification of lipid composition is another contributor to lipotoxicity, and recent studies are aimed at searching for specific metabolic changes as potential signatures of development of HCC in patients with NAFLD [57]. For example, some studies show that, during natural history of progression from normal liver to NAFLD or NASH, the ratio of polyunsaturated fatty acids (PUFAs) is increased in NASH, and phosphatidylcholine (PC) levels are reduced in both NAFLD and NASH, and based on these observations, it has been suggested that the LPA signaling axis may be one of the mechanism that is connecting hepatic steatosis to HCC [58–61].

#### 3.4. Microbiota: Intestinal flora dysregulation

The basis for the ongoing interest on the role of gut microbiota in progression of NAFLD was the observation of fatal NASH that occurred in patients undergoing jejunoileal bypass in bariatric surgery and the reversal after metronidazol therapy [62]. There are several evidences that demonstrate a high prevalence of small intestinal bacterial overgrowth in patients with NAFLD/NASH and that also demonstrate the role of microbiota modifications in the development of NAFLD and NASH [45]. Specific microflora changes may play an important role in progression of hepatic steatosis, especially in obese patients. In patients with NAFLD and NASH was observed a difference in microbiota composition compared with healthy population [63, 64]. The mechanisms implicated in the progression of gut microbiota-related NAFLD and NASH and HCC are: alteration of intestine permeability, persistent activation of innate immune system with consequent chronic inflammation, changes in bile acid metabolism [65].

Patients with NAFLD or NASH show increased levels of lipopolysaccharides (LPS), a known innate immune system activator, on serum confirming the inflammatory state associated with this conditions and alteration in gut permeability with disruption of intercellular tight junctions observed in patients with NAFLD can contribute directly to lipopolysaccharides action to the liver [65, 66].

All these findings were confirmed in human study wherein increased LPS-binding protein (LBP) levels were observed in obese patients with NAFLD and even more in obese patients with NASH, correlating with liver TNFα increased expression [67].

All these mechanisms show how changes in the microbiota, in combination with loss of innate immune sensors, may induce metabolic liver disorders.

Author details

Andra-Iulia Suceveanu1

Felix Voinea<sup>4</sup> and Adrian-Paul Suceveanu5

Ovidius University, Constanta, Romania

Metabolic Disease, Bucharest, Romania

Ovidius University, Constanta, Romania

University, Constanta, Romania

University, Constanta, Romania

References

2017;67:302-309

\*, Laura Mazilu<sup>2</sup>

\*Address all correspondence to: andrasuceveanu@yahoo.com

2893-2917. PMID: 21351269. DOI: 10.1002/ijc.25516

, Andreea-Daniela Gheorghe<sup>2</sup>

1 Faculty of Medicine, Department of Gastroenterology, Emergency Hospital of Constanta,

2 Faculty of Medicine, Department of Oncology, Emergency Hospital of Constanta, Ovidius

3 University of Medicine and Farmacy, Carol Davila, Department of Diabetes, Nutrition and

4 Faculty of Medicine, Department of Urology, Emergency Hospital of Constanta, Ovidius

5 Faculty of Medicine, Department of Internal Medicine, Emergency Hospital of Constanta,

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Gut microbiota also influences bile acid metabolisms mainly through the stimulation of the bile-acid-activated nuclear receptor and also by interacting with farnesoid X receptor (FXR) which induce excretion of bile acids from the liver and production of antimicrobial peptides [65].
