Evidence for a potential role of insufficient dietary fiber intake was also presented [82]

Evidence for a potential role of insufficient dietary fiber intake was also presented [82]. in later stages of NAFLD. On the basis of this literature review, this study proposed screening in individuals with the highest genetic or acquired risk of disease progression, for example, the SIRD subgroup, and developing treatment concepts targeting the earliest pathophysiolgical alterations, namely, adipocyte dysfunction and insulin resistance. Keywords: Fatty liver, Lipotoxicity, Inflammation, Fibrosis, Insulin resistance, Clinical trials Abbreviations ACCacetyl coenzyme A carboxylaseapoB100apolipoprotein B100ATPadenosine triphosphateBMIbody mass indexJNKc-Jun N-terminal kinaseChREBPcarbohydrate regulatory element-binding proteinCCRchemokine receptorsCD36cluster of differentiation 36DNLde novo lipogenesisDAGdiacylglycerolDPP-4idipeptidyl peptidase-4 (DPP-4) inhibitorsERendoplasmic reticulumECMextracellular matrixFXRfarnesoid X receptorFAfatty acidsFATPfatty acids transpondersFGFfibroblast growth factorFNDC5fibronectin type III domain-containing protein 5Ffibrosis stageGLP-1 RAglucagon-like peptide 1 (GLP-1) receptor agonistsGCKRglucokinase regulatory proteinHSChepatic stellate cellsIL-1interleukin 1IL-6interleukin 6LPSlipopolysaccharideLSECsliver sinusoidal endothelial cellsLYPLAL1lysophospholipase-like 1MRI-PDFFmagnetic resonance imagingCestimated proton density fat fractionMRSmagnetic resonance spectroscopyMTTPmicrosomal triglyceride transfer proteinNAFLDnonalcoholic fatty liver (NAFL) diseaseNASHnonalcoholic steatohepatitisPNPLA3patatin-like phospholipase domain-containing protein 3PPARperoxisome proliferator-activated receptorPUFApolyunsaturated fatty acidsPKCprotein kinase CRCTrandomized controlled trialROSreactive oxygen speciesRNAribonucleic acidSIRDsevere insulin-resistant diabetesSGLT2isodium glucose cotransporter (SGLT)-2 inhibitorsSREBP1csterol regulatory element-binding protein 1cSCD1stearoyl-CoA desaturase 1THRthyroid hormone receptorTNF-tumor necrosis factor-TLR4toll-like receptor-4TGF-transforming growth factor-TM6SF2transmembrane 6 superfamily member 2TAGtriacylglycerolT2DMtype 2 diabetes mellitusUPRunfolded protein responseVLDLvery low density lipoprotein 1.?Introduction Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, with a prevalence approaching 25% in the general population [1] and mainly affecting individuals with obesity and type 2 diabetes mellitus (T2DM) [2]. The spectrum of NAFLD encompasses different abnormalities, ranging from a simple increase in intrahepatic lipid content (steatosis, nonalcoholic fatty liver, NAFL) to nonalcoholic steatohepatitis (NASH) with various degrees of necrotic inflammation, fibrosis, and ultimately, cirrhosis [3]. NAFLD is not only associated with an increased risk of hepatocellular carcinoma but also cardiovascular diseases and complications related to T2DM, such as nephropathy and neuropathy [[4], [5], [6]]. Thus, delineating the mechanisms underlying the pathogenesis of NAFLD is crucial to managing NAFLD and its comorbidities. Concepts in the literature have suggested that NAFLD results from a double-hit lesion [7]. The first hit was considered the intrahepatic accumulation of fatty acids (FA), which increased the vulnerability of the hepatic cells to a variety of secondary insults, leading to inflammation and ultimately fibrosis [8]. Several observations have challenged this view, for example, by showing that inflammation may precede hepatic triacylglycerol (TAG) accumulation and that steatosis may protect from liver damage, suggesting multiple hits acting simultaneously rather than sequentially to drive NAFLD progression [9]. This review addresses mechanisms underlying the development and progression of NAFLD from studies in humans. Furthermore, no pharmacological treatment has been authorized for NAFLD [10], but recent evidence from well-designed randomized controlled trials (RCTs) points to the effectiveness of particular pharmacological agents already in use to treat T2DM [[11], [12], [13]]. Therefore, this review also summarizes current ideas to treat NAFLD in humans. 2.?Populations at risk Despite the general association among obesity, dysglycemia, and NAFLD, the presence of metabolic comorbidities coexisting with NAFLD varies substantially across populations. Inside a population-based cohort study of more than 4 million individuals, having a median follow-up period of 4.7 years, overweight and obese individuals without further metabolic abnormalities including diabetes, hypertension, and dyslipidemia, presented with a 3.3- and an almost 7-fold higher risk of incident NAFLD, respectively, than their normal-weight counterparts [14]. These findings underline the key role of body weight, before the development of further metabolic abnormalities. By contrast, obesity cannot be viewed as the sole criterion for the screening of NAFLD, because the prevalence of nonobese NAFLD varies in the general populace from 25% to 50% [15] and the presence of 1 metabolic abnormalities actually in the absence of obesity doubles the risk for NAFLD [14]. However, actually among individuals with known diabetes, the prevalence of NAFLD may differ markedly. A recent analysis of the German Diabetes Study (GDS) confirmed the presence of 5 diabetes subgroups.Pegbelfermin (BMS-986036), a pegylated subcutaneously administered recombinant FGF21 analog, decreased hepatic fat fraction inside a 16-week phase II study of 75 overweight/obese participants, with generally mild adverse events, who most frequently reported diarrhea and nausea [238] (Table?3). example, the severe insulin-resistant diabetes (SIRD) subgroup (cluster) and the presence of an increasing quantity of gene variants, seem to predispose for excessive risk of NAFLD and its accelerated progression. Recent medical tests have been regularly unsuccessful in halting or avoiding NAFLD progression, probably because of including unselected cohorts in afterwards stages of NAFLD partially. Based on this books review, this research proposed verification in people with the highest hereditary or acquired threat of disease development, for instance, the SIRD subgroup, and developing treatment principles targeting the initial pathophysiolgical alterations, specifically, adipocyte dysfunction and insulin level of resistance. Keywords: Fatty liver organ, Lipotoxicity, Irritation, Fibrosis, Insulin level of resistance, Clinical studies Abbreviations ACCacetyl coenzyme A carboxylaseapoB100apolipoprotein B100ATPadenosine triphosphateBMIbody mass indexJNKc-Jun N-terminal kinaseChREBPcarbohydrate regulatory element-binding proteinCCRchemokine receptorsCD36cluster of differentiation Sulfaclozine 36DNLde novo lipogenesisDAGdiacylglycerolDPP-4idipeptidyl peptidase-4 (DPP-4) inhibitorsERendoplasmic reticulumECMextracellular matrixFXRfarnesoid X receptorFAfatty acidsFATPfatty acids transpondersFGFfibroblast development factorFNDC5fibronectin type III domain-containing proteins 5Ffibrosis stageGLP-1 RAglucagon-like peptide 1 (GLP-1) receptor agonistsGCKRglucokinase regulatory proteinHSChepatic stellate cellsIL-1interleukin 1IL-6interleukin 6LPSlipopolysaccharideLSECsliver sinusoidal endothelial cellsLYPLAL1lysophospholipase-like 1MRI-PDFFmagnetic resonance imagingCestimated proton thickness fats fractionMRSmagnetic resonance spectroscopyMTTPmicrosomal triglyceride transfer proteinNAFLDnonalcoholic fatty liver organ (NAFL) diseaseNASHnonalcoholic steatohepatitisPNPLA3patatin-like phospholipase domain-containing proteins 3PPARperoxisome proliferator-activated receptorPUFApolyunsaturated fatty acidsPKCprotein kinase CRCTrandomized managed trialROSreactive air speciesRNAribonucleic acidSIRDsevere insulin-resistant diabetesSGLT2isodium blood sugar cotransporter (SGLT)-2 inhibitorsSREBP1csterol regulatory element-binding proteins 1cSCD1stearoyl-CoA desaturase 1THRthyroid hormone receptorTNF-tumor necrosis factor-TLR4toll-like receptor-4TGF-transforming development factor-TM6SF2transmembrane 6 superfamily member 2TAGtriacylglycerolT2DMtype 2 diabetes mellitusUPRunfolded proteins responseVLDLvery low thickness lipoprotein 1.?Launch Nonalcoholic fatty liver organ disease (NAFLD) may be the most common chronic liver organ disease worldwide, using a prevalence getting close to 25% in the overall inhabitants [1] and mainly affecting people with weight problems and type 2 diabetes mellitus (T2DM) [2]. The spectral range of NAFLD includes different abnormalities, which range from a simple upsurge in intrahepatic lipid content material (steatosis, non-alcoholic fatty liver organ, NAFL) to non-alcoholic steatohepatitis (NASH) with different levels of necrotic irritation, fibrosis, and eventually, cirrhosis [3]. NAFLD isn’t only associated with an elevated threat of hepatocellular carcinoma but also cardiovascular illnesses and complications linked to T2DM, such as for example nephropathy and neuropathy [[4], [5], [6]]. Hence, delineating the systems root the pathogenesis of NAFLD is essential to handling NAFLD and its own comorbidities. Principles in the books have recommended that NAFLD outcomes from a double-hit lesion [7]. The initial hit was regarded the intrahepatic deposition of essential fatty acids (FA), which elevated the vulnerability from the hepatic cells to a number of secondary insults, resulting in irritation and eventually fibrosis [8]. Many observations possess challenged this watch, for instance, by displaying that irritation may precede hepatic triacylglycerol (Label) accumulation which steatosis may guard against liver organ damage, recommending multiple hits performing simultaneously instead of sequentially to operate a vehicle NAFLD development [9]. This review addresses systems underlying the advancement and development of NAFLD from research in human beings. Furthermore, no pharmacological treatment continues to be accepted for NAFLD [10], but latest proof from well-designed randomized managed trials (RCTs) factors to the efficiency of specific pharmacological agents currently in use to take care of T2DM [[11], [12], [13]]. Hence, this review also summarizes current principles to take care of NAFLD in human beings. 2.?Populations in danger Regardless of the general association among weight problems, dysglycemia, and NAFLD, the current presence of metabolic comorbidities coexisting with NAFLD varies substantially across populations. Within a population-based cohort research greater than 4 million people, using a median follow-up amount of 4.7 years, overweight and obese individuals without further metabolic abnormalities including diabetes, hypertension, and dyslipidemia, offered a 3.3- and an almost 7-fold higher threat of incident NAFLD, respectively, than their normal-weight counterparts [14]. These results underline the main element role of bodyweight, prior to the advancement of additional metabolic abnormalities. In comparison, weight problems cannot be considered to be the only real criterion for the testing of NAFLD, as the prevalence of non-obese NAFLD varies in the overall inhabitants from 25% to 50% [15] and the current presence of 1 metabolic abnormalities also in the lack of weight problems doubles the chance for NAFLD [14]. Nevertheless, also among people with known diabetes, the prevalence of NAFLD varies markedly. A recently available analysis from the German Diabetes Research (GDS) confirmed the current presence of 5 diabetes subgroups (clusters) [16] by extensive phenotyping of 1105 human beings with recently diagnosed diabetes. These subgroups comprised furthermore to serious autoimmune diabetes, age-related.Anti-inflammatory drugs 10.3.1. appear to predispose for extreme threat of NAFLD and its own accelerated development. Recent clinical tests have been regularly unsuccessful in halting or avoiding NAFLD development, perhaps partly because of including unselected cohorts in later on phases of NAFLD. Based on this books review, this research proposed verification in people with the highest hereditary or acquired threat of disease development, for instance, the SIRD subgroup, and developing treatment ideas targeting the initial pathophysiolgical alterations, specifically, adipocyte dysfunction and insulin level of resistance. Keywords: Fatty liver organ, Lipotoxicity, Swelling, Fibrosis, Insulin level of resistance, Clinical tests Abbreviations ACCacetyl coenzyme A carboxylaseapoB100apolipoprotein B100ATPadenosine triphosphateBMIbody mass indexJNKc-Jun N-terminal kinaseChREBPcarbohydrate regulatory element-binding proteinCCRchemokine Sulfaclozine receptorsCD36cluster of differentiation 36DNLde novo lipogenesisDAGdiacylglycerolDPP-4idipeptidyl peptidase-4 (DPP-4) inhibitorsERendoplasmic reticulumECMextracellular matrixFXRfarnesoid X receptorFAfatty acidsFATPfatty acids transpondersFGFfibroblast development factorFNDC5fibronectin type III domain-containing proteins 5Ffibrosis stageGLP-1 RAglucagon-like peptide 1 (GLP-1) receptor agonistsGCKRglucokinase regulatory proteinHSChepatic stellate cellsIL-1interleukin 1IL-6interleukin 6LPSlipopolysaccharideLSECsliver sinusoidal endothelial cellsLYPLAL1lysophospholipase-like 1MRI-PDFFmagnetic resonance imagingCestimated proton denseness extra fat fractionMRSmagnetic resonance spectroscopyMTTPmicrosomal triglyceride transfer proteinNAFLDnonalcoholic fatty liver organ (NAFL) diseaseNASHnonalcoholic steatohepatitisPNPLA3patatin-like phospholipase domain-containing proteins 3PPARperoxisome proliferator-activated receptorPUFApolyunsaturated fatty acidsPKCprotein kinase CRCTrandomized managed trialROSreactive air speciesRNAribonucleic acidSIRDsevere insulin-resistant diabetesSGLT2isodium blood sugar cotransporter (SGLT)-2 inhibitorsSREBP1csterol regulatory element-binding proteins 1cSCD1stearoyl-CoA desaturase 1THRthyroid hormone receptorTNF-tumor necrosis factor-TLR4toll-like receptor-4TGF-transforming development factor-TM6SF2transmembrane 6 superfamily member 2TAGtriacylglycerolT2DMtype 2 diabetes mellitusUPRunfolded proteins responseVLDLvery low denseness lipoprotein 1.?Intro Nonalcoholic fatty liver organ disease (NAFLD) may be the most common chronic liver organ disease worldwide, having a prevalence getting close to 25% in the overall human population [1] and mainly affecting people with weight problems and type 2 diabetes mellitus (T2DM) [2]. The spectral range of NAFLD includes different abnormalities, which range from a simple upsurge in intrahepatic lipid content material (steatosis, non-alcoholic fatty liver organ, NAFL) to non-alcoholic steatohepatitis (NASH) with different examples of necrotic swelling, fibrosis, and eventually, cirrhosis [3]. NAFLD isn’t just associated with an elevated threat of hepatocellular carcinoma but also cardiovascular illnesses and complications linked to T2DM, such as for example nephropathy and neuropathy [[4], [5], [6]]. Therefore, delineating the systems root the pathogenesis of NAFLD is vital to controlling NAFLD and its own comorbidities. Ideas in the books have recommended that NAFLD outcomes from a double-hit lesion [7]. The 1st hit was regarded as the intrahepatic build up of essential fatty acids (FA), which improved the vulnerability from the hepatic cells to a number of secondary insults, resulting in swelling and eventually fibrosis [8]. Many observations possess challenged this look at, for instance, by displaying that swelling may precede hepatic triacylglycerol (Label) accumulation which steatosis may guard against liver organ damage, recommending multiple hits performing simultaneously instead of sequentially to operate a vehicle NAFLD development [9]. This review addresses systems underlying the advancement and development of NAFLD from research in human beings. Furthermore, no pharmacological treatment continues to be authorized for NAFLD [10], but latest proof from well-designed randomized managed trials (RCTs) factors to the effectiveness of particular pharmacological agents currently in use to take care of T2DM [[11], [12], [13]]. Therefore, this review also summarizes current ideas to take care of NAFLD in human beings. 2.?Populations in danger Regardless of the general association among weight problems, dysglycemia, and NAFLD, the current presence of metabolic comorbidities coexisting with NAFLD varies substantially across populations. Inside a population-based cohort research greater than 4 million people, using a median follow-up amount of 4.7 years, overweight and obese BPES1 individuals without further metabolic abnormalities including diabetes, hypertension, and dyslipidemia, offered a 3.3- and an almost 7-fold higher threat of incident NAFLD, respectively, than their normal-weight counterparts [14]. These results underline the main element role of bodyweight, before the advancement of additional metabolic abnormalities. In comparison, weight problems cannot be thought to be the only real criterion for the testing of NAFLD, as the prevalence of non-obese NAFLD varies in the overall people from 25% to 50% [15] and the current presence of 1 metabolic abnormalities also in the lack of weight problems doubles the chance for NAFLD [14]. Nevertheless, even among people with known diabetes, the prevalence of NAFLD varies markedly. A recently available analysis from the German Diabetes Research (GDS) confirmed the current presence of 5 diabetes subgroups (clusters) [16] by extensive phenotyping of 1105 human beings with recently diagnosed diabetes. These subgroups comprised furthermore to.Many observations have challenged this view, for instance, by showing that inflammation may precede hepatic triacylglycerol (TAG) accumulation which steatosis may guard against liver organ damage, suggesting multiple hits operating simultaneously instead of sequentially to operate a vehicle NAFLD progression [9]. serious insulin-resistant diabetes (SIRD) subgroup (cluster) and the current presence of an increasing variety of gene variations, appear to predispose for extreme threat of NAFLD and its own accelerated development. Recent clinical studies have been often unsuccessful in halting or stopping NAFLD development, perhaps partly because of including unselected cohorts in afterwards levels of NAFLD. Based on this books review, this research proposed screening process in people with the highest hereditary or acquired threat of disease development, for instance, the SIRD subgroup, and developing treatment principles targeting the initial pathophysiolgical alterations, specifically, adipocyte dysfunction and insulin level of resistance. Keywords: Fatty liver organ, Lipotoxicity, Irritation, Fibrosis, Insulin level of resistance, Clinical studies Abbreviations ACCacetyl coenzyme A carboxylaseapoB100apolipoprotein B100ATPadenosine triphosphateBMIbody mass indexJNKc-Jun N-terminal kinaseChREBPcarbohydrate regulatory element-binding proteinCCRchemokine receptorsCD36cluster of differentiation 36DNLde novo lipogenesisDAGdiacylglycerolDPP-4idipeptidyl peptidase-4 (DPP-4) inhibitorsERendoplasmic reticulumECMextracellular matrixFXRfarnesoid X receptorFAfatty acidsFATPfatty acids transpondersFGFfibroblast development factorFNDC5fibronectin type III domain-containing proteins 5Ffibrosis stageGLP-1 RAglucagon-like peptide 1 (GLP-1) receptor agonistsGCKRglucokinase regulatory proteinHSChepatic stellate cellsIL-1interleukin 1IL-6interleukin 6LPSlipopolysaccharideLSECsliver sinusoidal endothelial cellsLYPLAL1lysophospholipase-like 1MRI-PDFFmagnetic resonance imagingCestimated proton thickness unwanted fat fractionMRSmagnetic resonance spectroscopyMTTPmicrosomal triglyceride transfer proteinNAFLDnonalcoholic fatty liver organ (NAFL) diseaseNASHnonalcoholic steatohepatitisPNPLA3patatin-like phospholipase domain-containing proteins 3PPARperoxisome proliferator-activated receptorPUFApolyunsaturated fatty acidsPKCprotein kinase CRCTrandomized managed trialROSreactive air speciesRNAribonucleic acidSIRDsevere insulin-resistant diabetesSGLT2isodium blood sugar cotransporter (SGLT)-2 inhibitorsSREBP1csterol regulatory element-binding proteins 1cSCD1stearoyl-CoA desaturase 1THRthyroid hormone receptorTNF-tumor necrosis factor-TLR4toll-like receptor-4TGF-transforming development factor-TM6SF2transmembrane 6 superfamily member 2TAGtriacylglycerolT2DMtype 2 diabetes mellitusUPRunfolded proteins responseVLDLvery low thickness lipoprotein 1.?Launch Nonalcoholic fatty liver organ disease (NAFLD) may be the most common chronic liver organ disease worldwide, using a prevalence getting close to 25% in the overall people [1] and mainly affecting people with weight problems and type Sulfaclozine 2 diabetes mellitus (T2DM) [2]. The spectral range of NAFLD includes different abnormalities, which range from a simple upsurge in intrahepatic lipid content material (steatosis, non-alcoholic fatty liver organ, NAFL) to non-alcoholic steatohepatitis (NASH) with several levels of necrotic irritation, fibrosis, and eventually, cirrhosis [3]. NAFLD isn’t only Sulfaclozine associated with an elevated threat of hepatocellular carcinoma but also cardiovascular illnesses and complications linked to T2DM, such as for example nephropathy and neuropathy [[4], [5], [6]]. Hence, delineating the systems root the pathogenesis of NAFLD is essential to handling NAFLD and its own comorbidities. Principles in the literature have suggested that NAFLD results from a double-hit lesion [7]. The first hit was considered the intrahepatic accumulation of fatty acids (FA), which increased the vulnerability of the hepatic cells to a variety of secondary insults, leading to inflammation and ultimately fibrosis [8]. Several observations have challenged this view, for example, by showing that inflammation may precede hepatic triacylglycerol (TAG) accumulation and that steatosis may protect from liver damage, suggesting multiple hits acting simultaneously rather than sequentially to drive NAFLD progression [9]. This review addresses mechanisms underlying the development and progression of NAFLD from studies in humans. Furthermore, no pharmacological treatment has been approved for NAFLD [10], but recent evidence from well-designed randomized controlled trials (RCTs) points to the efficacy of certain pharmacological agents already in use to treat T2DM [[11], [12], [13]]. Thus, this review also summarizes current concepts to treat NAFLD in humans. 2.?Populations at risk Despite the general association among obesity, dysglycemia, and NAFLD, the presence of metabolic comorbidities coexisting with NAFLD varies substantially across populations. In a population-based cohort study of more than 4 million individuals, with a median follow-up period of 4.7 years, overweight and obese individuals without further metabolic abnormalities including diabetes, hypertension, and dyslipidemia, presented with a 3.3- and an almost 7-fold higher risk of incident NAFLD, respectively, than their normal-weight counterparts [14]. These findings underline the key role of body weight, before the development of further metabolic abnormalities. By contrast, obesity cannot be viewed as the sole criterion for the screening of NAFLD, because the prevalence of nonobese NAFLD varies in the general populace from 25% to 50% [15] and the presence of 1 metabolic abnormalities even in the absence of obesity doubles the risk for NAFLD [14]. However, even among individuals with known diabetes, the prevalence of NAFLD may differ markedly. A recent analysis of the.MSDC-0602K, a mitochondrial pyruvate carrier inhibitor, is a second-generation insulin sensitizer designed to prevent side effects of PPAR agonists. risk of NAFLD and its accelerated progression. Recent clinical trials have been frequently unsuccessful in halting or preventing NAFLD progression, perhaps partly due to including unselected cohorts in later stages of NAFLD. On the basis of this literature review, this study proposed testing in individuals with the highest genetic or acquired risk of disease progression, for example, the SIRD subgroup, and developing treatment concepts targeting the earliest pathophysiolgical alterations, namely, adipocyte dysfunction and insulin resistance. Keywords: Fatty liver, Lipotoxicity, Inflammation, Fibrosis, Insulin resistance, Clinical trials Abbreviations ACCacetyl coenzyme A carboxylaseapoB100apolipoprotein B100ATPadenosine triphosphateBMIbody mass indexJNKc-Jun N-terminal kinaseChREBPcarbohydrate regulatory element-binding proteinCCRchemokine receptorsCD36cluster of differentiation 36DNLde novo lipogenesisDAGdiacylglycerolDPP-4idipeptidyl peptidase-4 (DPP-4) inhibitorsERendoplasmic reticulumECMextracellular matrixFXRfarnesoid X receptorFAfatty acidsFATPfatty acids transpondersFGFfibroblast growth factorFNDC5fibronectin type III domain-containing protein 5Ffibrosis stageGLP-1 RAglucagon-like peptide 1 (GLP-1) receptor agonistsGCKRglucokinase regulatory proteinHSChepatic stellate cellsIL-1interleukin 1IL-6interleukin 6LPSlipopolysaccharideLSECsliver sinusoidal endothelial cellsLYPLAL1lysophospholipase-like 1MRI-PDFFmagnetic resonance imagingCestimated proton density fat fractionMRSmagnetic resonance spectroscopyMTTPmicrosomal triglyceride transfer proteinNAFLDnonalcoholic fatty liver (NAFL) diseaseNASHnonalcoholic steatohepatitisPNPLA3patatin-like phospholipase domain-containing protein 3PPARperoxisome proliferator-activated receptorPUFApolyunsaturated fatty acidsPKCprotein kinase CRCTrandomized controlled trialROSreactive oxygen speciesRNAribonucleic acidSIRDsevere insulin-resistant diabetesSGLT2isodium glucose cotransporter (SGLT)-2 inhibitorsSREBP1csterol regulatory element-binding protein 1cSCD1stearoyl-CoA desaturase 1THRthyroid hormone receptorTNF-tumor necrosis factor-TLR4toll-like receptor-4TGF-transforming growth factor-TM6SF2transmembrane 6 superfamily member 2TAGtriacylglycerolT2DMtype 2 diabetes mellitusUPRunfolded protein responseVLDLvery low density lipoprotein 1.?Introduction Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, with a prevalence approaching 25% in the general population [1] and mainly affecting individuals with obesity and type 2 diabetes mellitus (T2DM) [2]. The spectrum of NAFLD encompasses different abnormalities, ranging Sulfaclozine from a simple increase in intrahepatic lipid content (steatosis, nonalcoholic fatty liver, NAFL) to nonalcoholic steatohepatitis (NASH) with various degrees of necrotic inflammation, fibrosis, and ultimately, cirrhosis [3]. NAFLD is not only associated with an increased risk of hepatocellular carcinoma but also cardiovascular diseases and complications related to T2DM, such as nephropathy and neuropathy [[4], [5], [6]]. Thus, delineating the mechanisms underlying the pathogenesis of NAFLD is crucial to managing NAFLD and its comorbidities. Concepts in the literature have suggested that NAFLD results from a double-hit lesion [7]. The first hit was considered the intrahepatic accumulation of fatty acids (FA), which increased the vulnerability of the hepatic cells to a variety of secondary insults, leading to inflammation and ultimately fibrosis [8]. Several observations have challenged this view, for example, by showing that inflammation may precede hepatic triacylglycerol (TAG) accumulation and that steatosis may protect from liver damage, suggesting multiple hits acting simultaneously rather than sequentially to drive NAFLD progression [9]. This review addresses mechanisms underlying the development and progression of NAFLD from studies in humans. Furthermore, no pharmacological treatment has been approved for NAFLD [10], but recent evidence from well-designed randomized controlled trials (RCTs) points to the efficacy of certain pharmacological agents already in use to treat T2DM [[11], [12], [13]]. Thus, this review also summarizes current concepts to treat NAFLD in humans. 2.?Populations at risk Despite the general association among obesity, dysglycemia, and NAFLD, the presence of metabolic comorbidities coexisting with NAFLD varies substantially across populations. In a population-based cohort study of more than 4 million individuals, with a median follow-up period of 4.7 years, overweight and obese individuals without further metabolic abnormalities including diabetes, hypertension, and dyslipidemia, presented with a 3.3- and an almost 7-fold higher risk of incident NAFLD, respectively, than their normal-weight counterparts [14]. These findings underline the key role of body weight, before the development of further metabolic abnormalities. By contrast, obesity cannot be regarded as the sole criterion for the screening of NAFLD, because the prevalence of nonobese NAFLD varies in the general population from 25% to 50% [15] and the presence of 1.